Atherosclerosis-induced arterial erectile dysfunction: pathogenesis, diagnosis, and therapeutic strategies

Introduction

Erectile dysfunction (ED) is a common and complex disorder defined as the inability to obtain and maintain an erection sufficient for satisfactory sexual intercourse (1,2). It is the most common sexual dysfunction in men and is closely related to people’s physical and mental health; it reduces the quality of life of patients and their families and seriously affects family harmony. ED is categorized according to the pathophysiological mechanisms: psychological, endocrine, neurological, arterial, venous, and medical (1). The etiology of arterial ED is diversified. Many diseases such as atherosclerosis (AS), hypertension, hyperglycemia, hyperlipidemia, and other chronic diseases, as well as smoking and other bad lifestyle habits, may lead to impaired vascular function, which in turn may cause a lack of arterial blood supply, leading to ED (3). Atherosclerosis-induced erectile dysfunction (AED) is the common type and its etiology is subdivided into: AS, medical, traumatic, and mixed. Relevant studies have shown that AS is the most common (4,5). Early studies have pointed out that the main underlying factor in the etiology of organic ED is widely recognized as AS (6) (Figure 1).

Figure 1 Molecular mechanisms of ED due to atherosclerosis. Atherosclerosis leads to vascular endothelial damage, which reduces eNOS activity and inhibits NO synthesis (7), and the reduction in NO cGMP production in penile corpus cavernosum smooth muscle cells reduces cGMP production and thus fails to activate PKG, which leads to a failure to relax smooth muscle, and insufficient perfusion (8,9) (a core mechanism of ED). Increased ROS (e.g., superoxide anion) in atherosclerotic plaques directly inactivate NO and activate the NF-κB pathway, exacerbating inflammation (10). Oxidative stress leads to endothelial cell apoptosis, further reducing NO bioavailability. Atherosclerotic plaques release pro-inflammatory factors (TNF-α, IL-1β, IL-6), which activate endothelial cells and macrophages and promote the expression of adhesion molecules VCAM-1, ICAM-1 (11), exacerbating vascular inflammation and fibrosis. Inflammatory signals are amplified through the TLR4/MyD88/NF-κB pathway (12), which inhibits eNOS activity and promotes the release of vasoconstrictor factors (e.g., ET-1). Oxidative stress and inflammation in atherosclerosis activate the RhoA/ROCK pathway (8), leading to increased contractility of smooth muscle cells and inhibition of erection. ROCK phosphorylates MLC, which enhances smooth muscle contraction and antagonizes the diastolic effect of NO. Created in BioRender. 1, 1. (2025) https://BioRender.com/mok2opq. cGMP, cyclic guanosine monophosphate; ED, erectile dysfunction; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; MLC, myosin light chain; NO, nitric oxide; PKG, protein kinase G; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1.

In fact, ED and AS share common risk factors (such as diabetes, hypertension, hyperlipidemia, smoking, obesity, and sedentary lifestyle), and ED is due to the presence of a common etiology between the two (13). Multiple studies have shown that not only is AS an independent risk factor for ED, but ED itself is considered an early warning sign of cardiovascular disease (CVD). The pathologic process of AS as a CVD involves the long-term accumulation of lipids, inflammatory cells, etc. in the inner walls of blood vessels, which may lead to serious consequences such as myocardial infarction and stroke (14,15). AS is a systemic pathology that involves the cavernous artery of the penis, through which blood flow is reduced (16,17). In 2005 first described the so-called “arterial size hypothesis”, which suggests that the clinical manifestations of AS depend on the caliber of the affected vessels and that due to the progressive nature of the atherosclerotic disease, the persistence of AS increases the pathogenicity at the endothelial level with time. Number of organs are involved (18). Given the small caliber of the cavernous arteries, it is clear that ED is the first manifestation of AS in the vast majority of patients with vascular disease (19). This paper intends to investigate the mechanisms by which AS affects arterial erectile function in terms of the vascular endothelium.

Pathogenesis of arterial ED due to AS

The penis consists mainly of the corpus cavernosum and its vascular nerves. The cavernous body of the penis, as the core erectile organ, is wrapped by a dense connective tissue geomembrane (2–3 mm thick when flaccid, decreasing to 0.5 mm during erection), and the interior is a special structure containing smooth muscle and cavernous sinus. The blood supply originates from the dorsal penile artery that branches off the Internal iliac artery. During sexual arousal, the cavernous smooth muscle relaxes, the sinusoidal gap expands to reduce vascular resistance, and arterial blood flow surges (up to 8 times the flaccid state), resulting in an increase in intracavernous pressure; the distended cavernous body compresses the refluxing veins, and at the same time, mechanical compression produced by the stretching of the tunica albuginea further restricts venous reflux. This dual effect of blood retention increases the size of the penis and maintains its hardness.

The corpus cavernosum, as a highly vascularized tissue, severely affects erectile function once arterial lesions occur; at the same time, prolonged insufficient blood supply causes hypoxia of the corpus cavernosum, resulting in a state of stress, which can cause damage and fibrosis of the corpus cavernosum smooth muscle cells (SMCs), which further impairs erectile function. Through animal models, we found the pathophysiological changes of arterial ED: atherosclerotic lesions lead to narrowing of the lumen and impeding arterial inflow (16). Reduced oxygenation of erectile tissue and production of gaseous metabolites ultimately impair endothelium-dependent diastolic function and overall smooth muscle contractility. In the absence of endothelial damage, the ED model fails to demonstrate endothelial dysfunction. The main mechanisms of arteriogenic ED and AS can be explained by two components: structural and functional changes. Structural changes are caused by impaired arterial blood flow leading to hypoxia and fibrosis. During this change, the growth transforming factor TGF-β plays a crucial role (8,20). In previous studies, arterial ligation or partial blockage was a good model to show structural changes (21-23). However, these studies did not attempt to show functional changes associated with endothelial dysfunction. The key mechanism of endothelial dysfunction is nitric oxide synthase (NOS) (24,25). Nitric oxide (NO) is involved in anti-inflammatory, anti-platelet aggregation, and antioxidant functions (26-28). NOS consists of three subtypes, including neuronal NOS, endothelial NOS, and inducible NOS. Endothelial NOS is found in the endothelial cells of the cavernous arteries, and it is a key factor in the endothelial dysfunction mechanism. In addition, AS as well as CVDs are strongly associated with ED, as shown in Table 1.

Vascular endothelial damage

First, AS causes damage to the vascular endothelium. Damage to the vascular endothelium releases biologically active substances such as endothelin and prostaglandins, which further affect vascular tone and blood flow, ultimately adversely affecting erectile function (33-35). Secondly, AS also triggers an inflammatory response in blood vessels (11), leading to cell degeneration or even death, which prevents the endothelial cells of blood vessels from performing their function of regulating vascular tone and blood flow, thus altering vascular tone and blood flow and negatively impacting erectile function (36). Finally, AS causes narrowing of the lumen of the arteries, which reduces the amount of blood flowing into the corpus cavernosum, thus affecting erectile function.

Among them, vascular endothelial cell (VEC) mechanosensitive genes have a profound impact on AS, such as activation of krüppel-like transcription factors2/4 (KLF2/KLF4) may induce AS protection, and KLF2 and KLF4 are genes linked to vascular homeostasis and participate in modulating the expression of numerous anti-inflammatory, antioxidant, and antithrombotic genes within endothelial cells (37). KLF2 also modulates various pro-inflammatory, prothrombotic, and vasoconstrictive factors, including VCAM1, Monocyte chemoattractant protein-1 (MCP-1), E-selectin (SELE), and endothelin 1 (ET1). By recruiting transcriptional activators (38), KLF2 suppresses the activation of NF-kB and the expression of pro-inflammatory genes. It also inhibits inflammatory genes by counteracting the pro-inflammatory transcription factors NF-kB and AP-1 (39,40). In contrast, in a high-cholesterol setting, NF-κB expression is activated within endothelial cells. Specific inhibition of NF-kB in endothelial cells diminishes the expression of pro-inflammatory and pro-adhesion genes, as well as monocyte chemotactic proteins, thereby reducing macrophage recruitment and stabilizing atherosclerotic plaques (41). KLF2 enhances the nuclear localization of NRF2 (42), which is crucial for regulating antioxidant levels and conferring resistance to AS by stabilizing shear stress (43,44). Pulsed laminar flow shear stress (PLSS) down-regulates circRNA-LONP2 expression and inhibits oxidative stress and endothelial inflammation by activating the miR-200a-3p-mediated NRF2/HO-1 signaling pathway, thereby inhibiting the development of AS (45), and preventing excessive reactive oxygen species (ROS)/reactive nitrogen production, which is required to promote AS gene expression (46). Dysregulation of endothelial mechanistic genes may lead to endothelial damage to the point of AS, and although vascular endothelial dysfunction is a major cause of ED, endothelial dysfunction affects erectile function (EF) before atherosclerotic plaque formation. Thus, patients with ED may have significant bilateral stenosis of the internal iliac-internal pudendal arteries (II-IPA), which are the main source of blood supply to the penis, resulting in insufficient blood flow to the penis to the point of arterial erectile function (47,48).

In addition, AS leads to atrophy and fibrosis of SMCs within the corpus cavernosum (49), which affects corpus cavernosum engorgement and dilatation, further affecting erectile function (16). Studies have noted that in arterial ED, the corpus cavernosum displays lower oxygen tension (50). Ischemia ultimately leads to a decrease in penile cavernous smooth muscle and an increase in fibrosis, and a growing body of data suggests that ischemia also leads to structural alterations of the tunica albuginea (51), with an increase in its elastic sclerostin and collagenous components, and that these structural alterations can lead to alterations in function, which can affect venous occlusive mechanisms. Therefore simply increasing the blood supply does not completely resolve arterial ED. At the 4th International Consultation on Sexual Medicine in Paris in 2015, the panel of experts recommended that patients with arterial ED who are eligible for surgery should meet the following criteria: patients with arterial occlusive disease who are no more than 55 years of age, and whose ED is recently attributable to focal arterial occlusion, and who do not have significant risk factors such as diabetes mellitus (DM), smoking, etc. concomitant. Surgery may not be beneficial in patients with diabetes or vascular risk factors. There are several possible modalities for microvascular arterial bypass surgery. Current studies cannot prove that surgery is superior to other methods. For vascular repair of aortoiliac artery occlusive disease, the internal iliac artery should be preserved to reduce the risk of associated ED (52-54). In 2018, the American Urological Association (AUA) Guidelines Panel recommended that penile artery reconstruction be considered for young men with ED and focal pelvic/penile artery occlusion, as well as for young men without documented systemic vascular disease or venous occlusive dysfunction (Conditional Recommendation; Level of Evidence: Grade C) (55). The European Association of Urology guidelines on ED, premature ejaculation, penile curvature, and abnormal erections recommend that penile revascularization may be considered in young patients with pelvic or perineal trauma and confirmed AI on penile pharmacological arteriography (56). One study has shown that utilizing balloon endothelial stripping of the iliac arteries followed by a cholesterol diet produced diffuse pelvic AS and pelvic organ ischemia in rabbits and rats (57-60). This technique resulted in varying degrees of AS occlusive disease that appeared to spread from the site of endothelial stripping of the iliac arteries to the smaller pelvic arteries and eventually to the pubic, bladder, and cavernous arteries. The probability of forming new arterial side branches in this model appears to be small because of the diffuse nature of the AS process and the spread of occlusive disease to smaller arteries (58,60). This animal model reveals persistent ischemia in the penis (57,59), providing us with the opportunity to study functional changes, structural modifications, and downstream molecular biology as well as pathways in chronic pelvic ischemia chronic pelvic inflammatory disease (CPID). An animal model of AS-induced CPID was developed to mimic the human condition of pelvic AS and to help study the role of CPID in reproductive dysfunction (61,62). Structural and functional assessment of the CPID model suggests that moderate ischemia promotes smooth muscle contraction-responsive organization of the penile corpus cavernosum (57,59,61,62), whereas prolonged and severe ischemia leads to significant degenerative changes in SMCs and nerve fibers leading to contractile failure and ED ensues. In addition, the establishment of a novel erectile vascular dynamics visualization system that mimics the dynamic relaxation/contraction regulation process in the erectile response, which not only allows direct visual imaging of the cavernous blood sinus cavities to assess the dynamic changes in the cavernous space but also allows in-depth exploration of erectile pathophysiology, is expected to deepen the understanding of ED pathophysiology, which will contribute to new treatments in the future (63).

Cell death and repair

AS results in a lack of adequate blood supply to the corpus cavernosum, hypoxia of tissues within the corpus cavernosum, and initiation of an apoptotic program in the SMCs of the spongiosum. At the same time, AS also triggers the production of inflammatory factors, leading to the initiation of the pyroptosis program in SMCs (64,65). In addition, the tissue activates the cellular autophagy mechanism for repair in order to protect itself.

Apoptosis

Apoptosis refers to the autonomous and orderly death of genetically controlled cells in order to maintain the stability of the internal environment. Under hypoxic conditions, cavernous SMCs may undergo a process of autophagy, leading to mitochondrial edema and cell membrane lysis, and ultimately to the appearance of apoptotic vesicles. The cavernous sinus, the core functional unit of the penile corpus cavernosum, is composed of both SMCs and endothelial cells, with the smooth muscle component accounting for approximately 45%, and is a key structure in maintaining erectile function. Studies have shown that excessive apoptosis of smooth muscle and endothelial cells directly leads to ED (20,66,67): smooth muscle apoptosis: a decrease in the number of cells prevents the cavernous sinus from expanding efficiently, triggering venous ED; endothelial cell apoptosis: leading to a decrease in endothelial nitric oxide synthase (eNOS) activity and a decrease in NO synthesis, which weakens vasodilatory capacity. Existing ED therapeutic agents (e.g., PDE5 inhibitors) work mainly by promoting smooth muscle relaxation, but in the case of severe apoptosis (e.g., in patients with DM or neurologic injury), the therapeutic effect is significantly reduced due to insufficient numbers of target cells. Emerging evidence highlights the role of vascular smooth muscle apoptosis in ED progression. For instance, in diabetic ED models, hyperglycemia-induced oxidative stress accelerates mitochondrial dysfunction and caspase-3 activation, leading to irreversible smooth muscle loss. Therapeutic strategies targeting apoptotic pathways (e.g., Bcl-2 inhibitors) or enhancing endothelial repair (e.g., PDE5 inhibitors combined with statins) show promise in restoring erectile function, and this mechanism has become a core direction in the study of ED pathology. Therefore, early intervention of apoptosis can not only accelerate the recovery of erectile function but also prevent the progression of fibrosis, providing new ideas for ED treatment.

Cellular pyroptosis (68)

Cellular pyroptosis also known as cellular inflammatory necrosis, is a specific form of programmed cell death. It differs from apoptosis in that it is primarily characterized by rupture of the cell membrane and release of cellular contents, which triggers an intense inflammatory response. Cellular pyroptosis is usually initiated by the activation of inflammatory caspases (e.g., caspase-1, caspase-4, caspase-5, and caspase-11). These caspases are activated following the formation of the inflammasome, a process that usually involves the activation of the Gasdermin family of proteins (Figure 2), particularly the Gasdermin D (GSDMD) proteins (72,73), Activated inflammatory caspases cleave Gasdermin family proteins, such as GSDMD, resulting in the release and insertion of its N-terminal fragment into the cell membrane, forming pores. These pores lead to the disruption of the integrity of the cell membrane, which in turn causes the release of cellular contents. Inflammatory mediators and cell contents released during cellular pyroptosis activate surrounding immune cells, leading to increased inflammatory response, and excessive inflammatory response may also lead to tissue damage and disease, such cellular pyroptosis can then lead to spongiocyte death. AS, a systemic inflammatory disorder, involves VECs, SMCs, and macrophages in its development. These cells participate in the inflammatory process and can undergo pyroptosis, a significant form of cell death that responds to cellular infections by initiating an inflammatory response. Notably, impaired endothelial homeostasis has been identified as a pivotal contributor to ED progression, particularly in vascular etiology (74). Analysis of AS plaques from patients who underwent carotid endarterectomy showed that the expression of proteins related to focal death was increased, with stable plaques exhibiting significantly lower expression levels of these proteins compared to unstable plaques (75), which suggests that cellular focal death is closely related to the stability of AS plaques and that the formation of AS also promotes cellular focal death, and that the release of inflammatory factors may promote spongiotic cellular focal death (76,77). It is well known that dysfunction and death of VECs are the initiating link in the development of AS. ROS and oxidized low-density lipoproteins are direct activators of nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) (78), and both can lead to VEC damage (79). In atherosclerotic plaques, NLRP3 inflammasome activation triggers caspase-1-dependent release of pro-inflammatory cytokines [e.g., interleukin (IL)-1β, IL-18] and GSDMD-mediated pyroptosis. This cascade amplifies endothelial inflammation, which is further exacerbated by Recombinant High Mobility Group Protein 1 (HMGB1)-RAGE interaction. Specifically, HMGB1 binding to RAGE activates NF-κB signaling, driving expression of adhesion molecules (vascular cell adhesion molecule-1, VCAM-1; intercellular adhesion molecule-1, ICAM-1) and perpetuating vascular dysfunction.

Figure 2 Cellular pyroptosis pathway. Cellular juxtaposition is a novel regulator of pro-inflammatory cell death (69). In the caspase1-dependent cellular juxtaposition pathway, cells can activate inflammatory vesicles in response to multiple factors triggering juxtaposition by activating the corresponding inflammatory vesicles (including NLRP3, AIM2, or pyrin) through the action of PAMPs and DAMPs; NLRP3 recruits ASCs and the precursor caspase-1 through a variety of pathways (70), leading to caspase-1 activation and the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18. Cleavage of inflammatory cysteines forms GSDMD-N (71), which triggers the rupture of cell membranes and promotes the release of inflammatory factors, cell swelling, and pyroptosis. ASC, apoptosis-associated speck-like protein containing a CARD; GSDMD, Gasdermin D; IL, interleukin.

Cellular autophagy (46)

Cellular autophagy (80,81) is a conserved catabolic process involving lysosomal degradation of cytoplasmic components, including misfolded proteins and dysfunctional organelles. This mechanism is orchestrated by autophagy-related genes (ATGs), which maintain cellular homeostasis under stress conditions such as hypoxia or nutrient deprivation. In the context of AED, dysregulated autophagy exacerbates cavernosal smooth muscle apoptosis and fibrosis, further impairing erectile function (81,82). Autophagy is closely associated with changes in VS.MC. Moderate autophagy facilitates plaque stabilization (82,83), but defective or excessive autophagy exacerbates AS development (84-86). Cytosolic autophagy, a key mechanism for maintaining intracellular homeostasis (87), may protect spongiotic smooth muscle and endothelial cells from damage caused by oxidative stress or metabolic disorders (e.g., DM) by removing damaged mitochondria or misfolded proteins. It has been shown that impaired autophagy may exacerbate endothelial cell apoptosis and affect NO synthesis, thereby reducing spongiotic expansion capacity.

Molecular mechanisms

The findings show that many molecules are associated with arterial ED caused by AS.

TGF-β: fibrosis is scarring and tissue hardening caused by excessive deposition of extracellular matrix (ECM) proteins by myofibroblasts in response to chronic inflammation (88-90). TGF-β is a multifunctional cytokine that plays a key role in fibrosis, leading to tissue hardening by promoting ECM synthesis by fibroblasts and inhibiting ECM degradation (91,92). Inflammatory stimuli induce a response in fibroblasts. In the spongiosa, sustained damage to the vascular endothelium in AS leads to a pathological over accumulation of ECM proteins with enhanced myofibroblast activity (93), which in turn triggers a chronic inflammatory milieu of macrophage and immune cell infiltration (94), with cytokines and growth factors being released in large quantities, among which TGF-β is a key effector in the fibrotic process (92,95,96), which possesses a non-TGF-β-SMAD pathway (Figure 3) and TGF-β-SMAD pathways (100,102-104), while activation of the TGF-β-SMAD2/3 signaling pathway (Figure 4) (107), with up-regulation of target gene expression, further enhances myofibroblast differentiation and ECM protein production and secretion. The balance of cavernous smooth muscle and connective tissue is disrupted and cavernous fibrosis occurs, leading to ED (108,109).

Figure 3 Non-canonical Smad-independent pathway. There are non-classical pathways for TGF-β signaling, in which the Erk/MAPK signaling pathway is involved in downstream signaling. The TGF-β receptor, upon phosphorylation, recruits ShcA, Grb2, and Sos. The Grb2/Sos complex activates Ras, which in turn triggers gene regulation through Raf, MEK1/2, and Erk1/2. In addition, TGF-β signaling activates Akt through PI3K, which regulates translation through mTOR (97). In addition, TGF-β signaling activates Akt through PI3K, which regulates translation through mTOR. Akt can also be activated through non-classical pathways. RhoA and ROCK can also be regulated by TGF-β in a Smad-independent manner. TGF-β (98,99) mediates EMT in cancer cells by interfering with cell adhesion and epithelial gene expression and increasing mesenchymal protein expression. Smad-dependent pathway induces the expression of SNAIL, SLUG, ZEB, and TWIST transcription factors, which mediate pontine dissociation. Smad-non-dependent pathway facilitates cytoskeletal remodeling through ERK activation and Rho-GTPase (100,101). ERK enhances the Smad transcriptional activity and assists in TGF-β/Smad-dependent EMT. TGF-β receptor phosphorylation also activates non-classical pathways such as Rho, PI3K/Akt and Grb2/SOS. EMT, epithelial-mesenchymal transition; mTOR, mechanistic target of rapamycin; TGF-β, transforming growth factor-β.

Figure 4 Canonical Smad-dependent pathway. Typically, activated TGF-β binds to TGF-β receptor type II, which recruits and phosphorylates TGF-βR1 (100). Activated TGF-βR1 phosphorylates the C-terminal serine residues of R-Smads Smad2 and Smad3, and the R-Smads dissociate from the type I receptor, form a heterotrimeric complex with co-Smad (Co-Smad) Smad4 in early endosomes, and translocate into the nucleus (105). Within the nucleus, the Smad complex interacts with transcription factors, chromatin-binding proteins, transcriptional coactivators, and co-inhibitors and physically binds to target genes to perform transcriptional regulation at the genomic level, leading to different roles for the TGF-β classical pathway in different environments. Smad also has another member, called I-Smad, such as the classical example Smad7 (106), which negatively regulates the classical pathway by competing with Smad 2/3 for binding to the type I receptor and acting as negative feedback to attenuate TGF-β/Smad signaling. In a typical signaling cascade, activated TGF-βR1 leads to phosphorylation of Smad2/3. The Smad2/3 complex then binds to Smad4 and translocates to the nucleus, where it induces gene transcription. Negative feedback of Smad7 on TGF-βR1 inhibits signaling. ECM, extracellular matrix; I-Smad, inhibitory Smad; R-Smads, receptor-associated Smads; TGF-β, transforming growth factor-β; TGF-βR, TGF-β receptor.

The NOS-cGMP-PDE5 pathway (Figure 5) constitutes an important pathophysiological basis for different types of ED (108,114,115). Furthermore, its significance is supported by a growing body of evidence (116,117). The discovery of the NOS-cGMP-PDE5 pathway has been shown to be critical for the normal physiological function and pathophysiology of ED (118,119). NO is released by endothelial cells and neurons in penile tissues and binds to soluble guanylate cyclase to increase the production of cGMP, which in turn activates the protein kinase G (PKG) to form a complex cGMP/PKG-induced relaxation of penile corpus cavernosum smooth muscle (120,121), with the ensuing excessive arterial blood flow, constitutes the basic principle of penile erection (122). The vascular endothelium is a single layer of flat epithelial cells, and endothelial cells not only provide a barrier, but are also metabolic endocrine tissues that secrete and metabolize a wide range of vasoactive substances, which are essential for regulating vascular tone and maintaining blood homeostasis, and thus are important targets for the action of numerous AS risk factors (123,124). Changes in NO content and bioactivity can reflect the state of endothelial function, and low NO function is closely related to the damage process of endothelial cells (123). After the development of AS, the vascular endothelium is damaged and the NO content decreases, which leads to the deficiency of the initiating factor of the NO-cGMP-PDE5 pathway, and then triggers ED.

Figure 5 NO-cGMP-PDE5 pathway. The NO/cGMP/PKG transduction signaling pathway.NO is produced by oxidation of L-arginine by NOS and serves as an activator of sGC (110,111), which induces cGMP production via phosphorylation of GTP. Many NO donors (endogenous and exogenous) enhance the bioavailability of NO, leading to a massive activation of the cGMP pathway. cGMP can inhibit and enhance cAMP production in smooth muscle cells by metabolic inhibition of the cAMP inhibitor PDE3 and by stimulation of PDE2 (112), which degrades cAMP, and thus NO/cGMP can be induced by either a cGMP-dependent PKG-dependent (NO-cGMP-PKG) or a non-dependent (NO-cGMP-cGMP binds to three different effector proteins), PKG, PDE, and cyclic nucleotide-gated cation channels (CNG channels), which mediate sensory transduction in cells. PDE5 is a cGMP-specific phosphodiesterase that targets and inhibits the critical NO/cGMP/PKG signaling pathway (113). In the presence of a PDE5i, PDE5 is unable to perform its hydrolytic function and allows cGMP to continue its platelet inhibitory function via PKG. AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GTP, guanosine-5'-triphosphate; NO, nitric oxide; NOS, NO synthase; PDE2, phosphodiesterase 2; PDE3, phosphodiesterase 3; PDE5, phosphodiesterase 5; PDE5i, PDE5 inhibitor; PKA, protein kinase A; PKG, protein kinase G; PS, lipopolysaccharide; sGC, soluble guanylate cyclase.

Endothelial-smooth muscle crosstalk

The interplay between eNOS dysfunction and cavernosal smooth muscle fibrosis is a hallmark of atherosclerotic ED. Reduced eNOS activity diminishes NO bioavailability, while TGF-β-driven collagen deposition stiffens the corpus cavernosum, collectively impairing vasodilation. Mechanistically, endothelial-derived HMGB1 activates RAGE on adjacent SMCs, promoting RhoA/ROCK pathway activation and calcium sensitization. This dual dysfunction (impaired NO relaxation + enhanced contractility) underlies the hemodynamic failure in arterial ED (20,108).

Current status of epidemiology and diagnosis and treatment of AS-related ED

Epidemiological status

Epidemiological studies have demonstrated a high global prevalence and incidence of ED (125). For instance, the Massachusetts Male Aging Study (MMAS) reported an overall ED prevalence of 52% among non-institutionalized men aged 40–70 years in the Boston area (126), with specific prevalence rates of 17.2% (mild), 25.2% (moderate), and 9.6% (complete ED), respectively. The Cologne Study further revealed an ED prevalence of 19.2% in males aged 30–80 years, accompanied by a marked age-dependent escalation from 2.3% to 53.4% (127,128). Longitudinal data indicated an ED incidence rate of 26 cases per 1,000 person-years in the MMAS cohort, whereas a Dutch study with a mean follow-up duration of 4.2 years documented an incidence of 19.2 cases per 1,000 person-years (129). Notably, a cross-sectional study of individuals seeking initial medical consultation for newly diagnosed ED revealed that approximately 25% of participants were under 40 years of age, with nearly half of these young patients presenting with severe ED (130). The AUA guidelines indicate that the prevalence of ED significantly increases with age (131). Contemporary epidemiological studies using validated instruments (IIEF/IIEF-5) reveal substantially higher rates in younger populations than previously recognized, affecting 28–36% of men under 40 years old (132,133), while rates remain elevated in older adults (50–100% over 70 years) (131). Globally, ED burden demonstrates marked regional heterogeneity, with prevalence ranging from 13.1% in Asian cohorts to 76.5% in European populations (132,134). Among CVD patients, pooled prevalence reaches 62.6% [95% confidence interval (CI): 49.8–73.8%] (135), underscoring its comorbidity burden. Major risk factors include CVD, diabetes, obesity, hypertension, hypercholesterolemia, smoking, physical inactivity, and psychological factors such as depression and anxiety. ED significantly impairs patients’ quality of life, mental health, and interpersonal relationships.

The current situation of AS and related diseases in Asia is severe and complex and has become a central challenge in public health. As the main pathological basis of CVD, the prevalence of AS is intertwined with multiple risk factors, forming an “invisible storm”—more than 80% of the approximately 330 million CVD patients in China are directly related to the process of AS, and the resulting ischemic heart disease and stroke constitute the leading cause of death in urban and rural areas. Ischemic heart disease and stroke constitute the leading cause of death in both urban and rural areas. The spread of this disease is deeply rooted in social change: a diet high in salt and fat (the ratio of fat to energy supply in rural areas exceeds 30%), a sedentary lifestyle (the average daily sedentary time for adults reaches 3.2 hours), exposure to tobacco (the smoking rate of males exceeds 50%), and air pollution [the average annual concentration of PM_2.5 is still higher than the World Health Organization (WHO) standard] constitute a “quadruple toxic chain”. What is more worrying is the trend of metabolic disorders at a younger age—the obesity rate of children has doubled in ten years, and the rate of dyslipidemia among adolescents has reached 20.3%, which is laying the groundwork for the outbreak of diseases in the future. In addition, among 10,733,975 Chinese participants, the estimated prevalence of increased carotid intima-media thickness (cIMT) was 26.2%, carotid plaque (CP) was 21.0%, and carotid stenosis (CS) was 0.56%. Approximately one-quarter of Chinese adults had increased cIMT or CP, and the prevalence of carotid atherosclerosis (CAS) varied significantly among different provinces and geographic regions of China, with higher prevalence in northern and central regions. The prevalence of all CAS grades was higher among older adults, men, individuals living in the north, and individuals with co-morbid conditions such as hypertension, DM, dyslipidemia, and metabolic syndrome, and most CVD risk factors were independent risk factors for all CAS stages. For example, the associations of hypertension with increased cIMT, CP, and CS were 1.60, 1.62, and 1.48, respectively (95,96). The prevalence of ED in Chinese men has been on the rise in recent years (136). Moreover, AS and ED share a number of pathophysiologic mechanisms, including endothelial dysfunction, inflammation, and AS. These mechanisms play an important role in the development of ED and are particularly prominent in vascular ED. Endothelial dysfunction is recognized as an early marker of both AS and ED. ED and AS share common risk factors such as DM, obesity, metabolic syndrome, dyslipidemia, smoking, and physical inactivity. These risk factors play a key role in the development of AS and are also strongly associated with the development of ED (16).

Current status of medical treatment

Integrating drug therapy and conventional treatment

According to European Association of Urology (EAU) guidelines and AUA guidelines, first-line treatment involves lifestyle adjustments: weight loss, smoking cessation, and regular exercise (especially for patients with metabolic syndrome) (15,137-143). PDE5 inhibitors (such as sildenafil, tadalafil, etc.) are the preferred drugs (144), with an efficacy rate of about 70%. Psychological counseling or sex therapy can be combined for patients with psychological or mixed ED. Additionally, low-intensity extracorporeal shockwave therapy (Li-ESWT) is listed as a first-line option by the EAU, especially for vascular ED (145-147). A meta-analysis of 12 randomized trials revealed that combining PDE5 inhibitors with atorvastatin significantly improves erectile function in patients with hyperlipidemia [odds ratio (OR) =2.1, 95% CI: 1.5–3.0]. This synergy arises from statin-mediated endothelial repair (via eNOS upregulation) and PDE5 inhibitor-enhanced NO-cGMP signaling. Notably, patients with severe arterial stenosis [penile artery peak systolic velocity (PSV) <25 cm/s] showed a 68% higher response rate to combination therapy compared to monotherapy (P<0.01) (148).

The relationship between non-steroidal anti-inflammatory drugs (NSAIDs), platelets, and ED involves complex and controversial mechanisms. NSAIDs, such as aspirin, can reduce the synthesis of prostaglandins (e.g., PGI2, PGE2) through inhibiting the cyclooxygenase (COX) pathway (149-151). These vasodilatory substances promote cavernosal smooth muscle relaxation and blood perfusion by activating the cyclic adenosine monophosphate (cAMP) pathway, and their reduction may potentially disrupt the hemodynamic basis of erection. Mendelian randomization studies have shown a significant positive association between genetically inferred aspirin use and ED risk (OR =20.896, 95% CI: 2.077–2.102×10², P=0.01), suggesting a causal relationship. However, in healthy rat models, short-term or long-term use of aspirin (10–150 mg/kg/d) did not significantly alter erectile function parameters (e.g., mICP, mICP/MAP ratio), possibly due to compensation by the NO-cGMP pathway for prostaglandin deficiency.

Platelets play a dual role in ED: their activated state releases vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other factors that promote cavernous nerve regeneration and angiogenesis. Conversely, NSAIDs inhibit platelet activation, potentially weakening this endogenous repair mechanism. In a rat model of bilateral cavernous nerve crush (BCNC)-induced ED, aspirin (10 mg/kg/d) failed to improve erectile function and further inhibited prostaglandin synthesis, indicating that NSAIDs may exacerbate ED in pathological states by suppressing platelet function.

In contrast to NSAIDs, platelet-rich plasma (PRP) (149,151) enhances PDGF release through centrifugation and activation, demonstrating promising effects in improving ED in animal and preliminary clinical studies (152-154). For example, PRP promotes axonal regeneration after cavernous nerve injury in rats, increasing erectile function scores [e.g., intracavernosal pressure (ICP)/mean arterial pressure ratio]. In randomized controlled trials, the rate of achieving the minimal clinically important difference (MCID) in the PRP group (69%) was significantly higher than that in the placebo group (27%) at 6 months. This discrepancy highlights the bidirectional role of platelet function regulation in ED: inhibition (e.g., by NSAIDs) may induce or worsen ED, while activation (e.g., by PRP) improves the condition through repair mechanisms.

Current research has limitations, including differences in NSAID dosages (animal experiments vs. clinical use), heterogeneity of study populations (healthy individuals vs. those with diabetes/CVDs), and undefined specificity of NSAID types (e.g., aspirin vs. other NSAIDs). Future studies should further investigate the dose-response relationship of NSAIDs in different etiologies of ED and the correlation between platelet activation levels and ED severity to accurately evaluate the risks of NSAIDs and the therapeutic potential of PRP.

Second-line treatment includes the use of vacuum erection devices (VED) (155,156) suitable for patients who are unresponsive to or contraindicated for medication (such as those using nitrate drugs). Urethral prostaglandin E1 suppositories (MUSE) or intracavernosal injections (ICIs) (such as alprostadil, PGE1) have an efficacy rate of up to 80%, but patients need to be trained in injection techniques (157,158).

Testosterone replacement therapy: The AUA strictly limits this to patients diagnosed with hypogonadism (total testosterone <300 ng/dL), while the EAU also recommends trying it for patients with borderline low levels (300–350 ng/dL) (159,160).

Third-line treatment involves penile prosthesis implantation (161-164): suitable for patients who have failed drug/device treatments and whose quality of life is severely affected by ED, with patient satisfaction rates exceeding 90%. The EAU recommends inflatable prostheses as the first choice, while the AUA emphasizes the need for thorough preoperative assessment (such as diabetes control).

Lipoproteins, especially apolipoprotein B (apoB)-containing lipoproteins, are associated with the development of AS, oxidized low-density lipoprotein (ox-LDL) promotes the progression of AS, and high-density lipoprotein (HDL) contributes to the removal of cholesterol from macrophages and inhibits foam cell formation. These findings suggest that lipoproteins may serve as biomarkers for predicting AS risk or as novel therapeutic targets (165). Conventional statins are the treatment of choice for low-density lipoprotein cholesterol (LDL-C) lowering in patients with atherosclerotic cardiovascular disease (ASCVD), but many patients fail to achieve target LDL-C levels despite treatment with low/moderate intensity statins. In contrast, low/moderate-intensity statin combination therapy with ezetimibe is more effective than high-intensity statin monotherapy in lowering LDL-C levels and has a lower incidence of myalgia and discontinuation rate due to adverse events while improving the rate of LDL-C goal attainment (148,166). Recent advances in traditional Chinese medicine (TCM) pharmacology have systematically elucidated the therapeutic mechanisms against endothelial dysfunction and AS. The Danshen-Shanzha formula (DSF), a canonical TCM preparation, demonstrates multi-target efficacy in ASCVDs through its bioactive constituents including tanshinones, phenolic acids, and triterpenoids, as evidenced by network pharmacology analysis and experimental validation (167,168). Specifically, Fufang Danshen Tablet (FDT) transcriptionally suppresses P-selectin (SELP) and CCL2 expression, thereby inhibiting leukocyte-endothelial adhesion and subintimal migration—a dual anti-inflammatory and anti-atherogenic mechanism corroborated by systematic pharmacological studies (169). Concurrently, Ganoderma lucidum polysaccharides (GLP) mitigate oxidative stress via NADPH oxidase inhibition while modulating lipid metabolism through PPAR-γ/LXR-α pathway activation, as demonstrated in preclinical AS models (170). These findings align with broader evidence that TCM natural products regulate inflammatory- oxidative stress crosstalk during atherosclerotic progression (171). Furthermore, baicalein orchestrates synergistic anti-atherosclerotic effects by stabilizing IκBα to inhibit NF-κB signaling, enhancing β-catenin nuclear translocation via GSK3β Ser9 phosphorylation, and promoting ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux, thereby suppressing macrophage foam cell formation and pro-inflammatory cytokine secretion-a mechanism validated by pharmacokinetic and immunomodulatory studies (168). Collectively, these TCM compounds exhibit endothelial-protective and plaque-stabilizing properties through multi-pathway regulation of vascular inflammation and lipid homeostasis (167-171). The effective treatment of endothelial injury facilitates the recovery of AED.

Advances in gene therapy and nanotechnology

Transcription factor EB (TFEB) plays an important role in the regulation of lipid homeostasis by promoting lipophagy, helping cells to degrade lipids, regulating genes related to lipid metabolism, and facilitating lipid efflux, thus contributing to the restoration of lipid homeostasis, and TFEB may be a potential target for the treatment of AS. Post-translational modifications are considered to be the main pathway to regulate TFEB activity and intracellular localization, but only phosphorylation modifications have been intensively studied, while other powerful regulatory mechanisms, such as acetylation, sumoylation, and ubiquitination, remain to be explored (168).

Targeted nanomedicine delivery system can effectively reduce the formation of atherosclerotic plaques, lower the level of inflammatory factors, and improve vascular function, such as VCAM-1 targeting, ICAM-1 targeting, E-selectin targeting, P-selectin targeting, and MCP-1 targeting for treatment, which provides a new way of thinking about AS treatment (167), AS treatment has a significant effect on ED improvement has a significant effect. Studies have shown that by effectively repairing vascular endothelial function, penile blood flow can be increased, contributing to ED recovery (170). The study identified a dual-responsive nanoparticle sensitive to low pH and ROS that was coated with a dextran shell for targeted delivery of astaxanthin, the antioxidant Szeto-Schiller 31 (SS-31) peptide, and the photoacoustic contrast agent PMeTPP-MBT. These nanoparticles were designed to target VCAM-1, which is overexpressed on the surface of activated endothelial cells, and CD44. Astaxanthin increases cholesterol efflux by upregulating ABCA1/G1, while SS-31 reduces endocytosis of oxidized LDL by inhibiting the expression of oxidized LDL receptor-1 (LOX-1)/CD36. Both astaxanthin and SS-31 have intrinsic anti-inflammatory properties and can reduce the levels of TNF-α and IL-6, and this dual action. These dual effects can effectively reduce atherosclerotic lesions, thereby favoring the improvement of ED (169). It was found that circRNA-LONP2 may be a new target for AS treatment. Down-regulation of circRNA-LONP2 inhibits oxidative stress and endothelial inflammation through activation of miR-200a-3p-mediated NRF2/HO-1 signaling pathway, which provides a new idea for the treatment of AS (45).

Cellular pyroptosis plays an important role in AS progression and thus has a corresponding effect on ED. The typical pathway of pyroptosis involves members of the NLRP3 family, while the atypical pathway involves the activation of caspase-11 (caspase-4/5 in humans). It has been discovered that VX-765, a pyroptosis inhibitor, is a selective small-molecule that functions by covalently modifying the catalytic site of caspase-1, thereby blocking its activation. By inhibiting caspase-1, VX-765 attenuates pyroptosis in the disease. In addition, the NLRP3 signaling pathway is a key step in pyroptosis, and MCC950 is a specific small molecule inhibitor that has been identified as an inhibitor of the NLRP3 inflammasome (171). MCC950, as a compound specifically inhibiting the NLRP3 inflammasome, was shown in studies to reduce the assembly and activation phases of the NLRP3 inflammasome through inhibition of the calcified nodules in vascular smooth muscle cells (VSMCs), MCC950 intervention also reduced the expression of inflammatory indicators NLRP3 and IL-1β, as well as the expression of indicators GSDMD and caspase-1 related to focal death, which attenuated the inflammatory response and focal death, and thus suppressed the calcification process in VSMCs, and therefore was effective in inhibiting AS with cellular focal death (76,77,172-174).

Summary and outlook

There are advances in the study of arterial ED and AS, particularly with the use of Superb microvascular imaging (SMI) technology (175,176). It uses an intelligent algorithm that efficiently separates low-speed flow signals from motion artifacts so that it can assess microvessels and the vessel distribution in detail, in the diagnosis of vascular ED, as well as the role of inflammation in ASCVD and the impact of Transient Receptor Potential Cation Channel Subfamily V Member 4 (TRPV4) calcium-permeable channels in AS valvular sclerosis, have greatly improved our understanding of these conditions and paved the way for more effective treatment strategies. By comprehensively addressing the multifactorial nature of these conditions, healthcare professionals can improve patient outcomes, enhance cardiovascular health, and optimize human health. The development of molecular biology techniques, where the molecular mechanisms of action are gradually appearing clearer, has clearly contributed to many advances in the level of research in the areas of erectile signaling pathways, SMC survival signaling, and spongy fibrosis. Despite significant advances in the areas of AS and ED research, such as the role of VECs in the formation of AS and the potential efficacy of sildenafil in the treatment of ED, the quest for a comprehensive understanding of the complexity of these disorders and the realization of effective treatments continues. The symbiotic relationship between arterial ED and AS emphasizes the importance of comprehensive treatment of patients with ED, urging a shift from a single urological perspective to broader cardiovascular therapies (177). Future research directions should be directed toward further development of the field by refining diagnostic methods, identifying new therapeutic targets, optimizing therapeutic strategies, and exploring emerging areas such as nanomedicine and regenerative approaches in the context of our growing understanding of the common pathophysiological mechanisms of arterial ED and AS. Future research could concentrate on the following directions to further elucidate the mechanisms and optimize the treatment of AED: developing innovative biomarkers (e.g., circulating endothelial cells and specific inflammatory factors) for early and precise diagnosis of AED; investigating gene editing technologies (e.g., CRISPR-Cas9 targeting and regulation of the TGF-β/Smad pathway) and intelligent nanomedicine delivery systems (e.g., VCAM-1-targeted drug-loaded nanoparticles) to enhance the precision of endothelial repair and anti-fibrotic therapy; conducting in-depth analyses of the interaction mechanisms between pyroptosis (e.g., NLRP3 inflammasome regulation) and autophagy dysregulation, and designing small molecule inhibitors (e.g., MCC950) or activators to interrupt pathological cascade reactions; integrating artificial intelligence (AI) with ultra-micro vascular imaging SMI technology to establish personalized diagnostic and therapeutic models while dynamically assessing vascular function and treatment responses; exploring the multi-target regulatory potential of active components in traditional Chinese medicine (e.g., Salvia miltiorrhiza polyphenols and GLP) to develop novel strategies for endothelial protection via the integration of traditional Chinese and Western medicine. Additionally, focusing on emerging fields such as the interplay between gut microbiota and vascular endothelium may offer new insights into the systemic inflammatory mechanisms underlying AED. Achieving breakthroughs in these areas will facilitate the transition of AED management from single symptomatic treatment to multi-level etiological intervention, ultimately improving cardiovascular and sexual health outcomes for patients.

Conclusions

AED is tightly linked to vascular endothelial dysfunction, with key mechanisms involving reduced eNOS activity, impaired NO-cGMP signaling, and TGF-β-mediated fibrosis. Clinical evidence confirms bidirectional associations between atherosclerotic indicators (e.g., peripheral arterial disease, cIMT) and ED, with ED independently predicting future cardiovascular events. Current therapies, such as PDE5 inhibitors combined with endothelial repair strategies, and emerging approaches like nanomedicine and targeted pyroptosis inhibition, show promise in improving endothelial function and erectile outcomes. This review underscores the need for a comprehensive, cardiovascular-focused approach to AED management, integrating mechanistic insights with multi-modal therapeutic strategies.

Acknowledgments

We wish to express our appreciation to Dr. Fan Zhao for providing insightful guidance on the preliminary direction and scope of this research during its early conceptualization phase.

Footnote

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-241/prf

Funding: This article was funded by the National Natural Science Foundation of China (No. 81771571) and the Science and Technology Project of Nantong, Jiangsu Province (No. MS2023020).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-241/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. MacDonald SM, Burnett AL. Physiology of Erection and Pathophysiology of Erectile Dysfunction. Urol Clin North Am 2021;48:513-25. [Crossref] [PubMed]
2. Leslie SW, Sooriyamoorthy T. Erectile Dysfunction. 2025.
3. Bertini A, Pozzi E, Fallara G, et al. The atherosclerotic cardiovascular disease risk score is a reliable tool to identify patients with arteriogenic erectile dysfunction. Andrology 2023;11:1451-9. [Crossref] [PubMed]
4. Liu G, Zhang Y, Zhang W, et al. Significance of detailed hematological parameters as markers of arteriogenic erectile dysfunction. Andrology 2022;10:1556-66. [Crossref] [PubMed]
5. Mei Y, Chen Y, Wang X, et al. Association between erectile dysfunction and the predicted 10-year risk for atherosclerosis cardiovascular disease among U.S. men: a population-based study from the NHANES 2001-2004. Front Endocrinol (Lausanne) 2024;15:1442904. [Crossref] [PubMed]
6. Jackson G. Erectile dysfunction and cardiovascular disease. Int J Clin Pract 1999;53:363-8. [Crossref] [PubMed]
7. Roy R, Wilcox J, Webb AJ, et al. Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential. Int J Mol Sci 2023;24:15200. [Crossref] [PubMed]
8. Kaya-Sezginer E, Celik A, Kirlangic OF. Elucidating the Signaling Pathways Involved in Erectile Dysfunction. Current Signal Transduction Therapy 2024;19:15-39. [Crossref]
9. Samidurai A, Xi L, Das A, et al. Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders. Annu Rev Pharmacol Toxicol 2023;63:585-615. [Crossref] [PubMed]
10. Yan R, Zhang X, Xu W, et al. ROS-Induced Endothelial Dysfunction in the Pathogenesis of Atherosclerosis. Aging Dis 2024;16:250-68. [PubMed]
11. Soehnlein O, Libby P. Targeting inflammation in atherosclerosis—from experimental insights to the clinic. Nature Reviews Drug Discovery 2021;20:589-610. [Crossref] [PubMed]
12. Wei X, Zhang F, Cheng D, et al. Free heme induces neuroinflammation and cognitive impairment by microglial activation via the TLR4/MyD88/NF-κB signaling pathway. Cell Commun Signal 2024;22:16. [Crossref] [PubMed]
13. Lue TF. Erectile dysfunction. N Engl J Med 2000;342:1802-13. [Crossref] [PubMed]
14. Miner M, Nehra A, Jackson G, et al. All men with vasculogenic erectile dysfunction require a cardiovascular workup. Am J Med 2014;127:174-82. [Crossref] [PubMed]
15. Vlachopoulos C, Jackson G, Stefanadis C, et al. Erectile dysfunction in the cardiovascular patient. Eur Heart J 2013;34:2034-46. [Crossref] [PubMed]
16. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-43. [Crossref] [PubMed]
17. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999;340:115-26. [Crossref] [PubMed]
18. Montorsi P, Ravagnani PM, Galli S, et al. The artery size hypothesis: a macrovascular link between erectile dysfunction and coronary artery disease. Am J Cardiol 2005;96:19M-23M. [Crossref] [PubMed]
19. Salvio G, Ciarloni A, Cutini M, et al. Hyperhomocysteinemia: Focus on Endothelial Damage as a Cause of Erectile Dysfunction. Int J Mol Sci 2021;22:418. [Crossref] [PubMed]
20. Hu D, Ge Y, Cui Y, et al. Upregulated IGFBP3 with Aging Is Involved in Modulating Apoptosis, Oxidative Stress, and Fibrosis: A Target of Age-Related Erectile Dysfunction. Oxid Med Cell Longev 2022;2022:6831779. [Crossref] [PubMed]
21. Hotta Y, Hattori M, Kataoka T, et al. Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction. J Sex Med 2011;8:705-11. [Crossref] [PubMed]
22. Shiota A, Hotta Y, Kataoka T, et al. Oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction. J Sex Med 2013;10:2423-9. [Crossref] [PubMed]
23. Hotta Y, Ohno R, Kataoka T, et al. Effects of chronic vardenafil treatment persist after end of treatment in rats with acute arteriogenic erectile dysfunction. J Sex Med 2012;9:1782-8. [Crossref] [PubMed]
24. Janaszak-Jasiecka A, Płoska A, Wierońska JM, et al. Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets. Cell Mol Biol Lett 2023;28:21. [Crossref] [PubMed]
25. Theofilis P, Sagris M, Oikonomou E, et al. Inflammatory Mechanisms Contributing to Endothelial Dysfunction. Biomedicines 2021;9:781. [Crossref] [PubMed]
26. Williams JK, Andersson KE, Christ G. Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED. Int J Impot Res 2012;24:91-100. [Crossref] [PubMed]
27. Ryu JK, Cho CH, Shin HY, et al. Combined angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia. Mol Ther 2006;13:705-15. [Crossref] [PubMed]
28. Ryu JK, Shin HY, Song SU, et al. Downregulation of angiogenic factors and their downstream target molecules affects the deterioration of erectile function in a rat model of hypercholesterolemia. Urology 2006;67:1329-34. [Crossref] [PubMed]
29. Wang G, Ni C. Association of erectile dysfunction and peripheral arterial disease in NHANES 2001-2004: a cross-sectional study. Front Endocrinol (Lausanne) 2024;15:1439609. [Crossref] [PubMed]
30. Rinkūnienė E, Gimžauskaitė S, Badarienė J, et al. The Prevalence of Erectile Dysfunction and Its Association with Cardiovascular Risk Factors in Patients after Myocardial Infarction. Medicina (Kaunas) 2021;57:1103. [Crossref] [PubMed]
31. Raheem OA, Su JJ, Wilson JR, et al. The Association of Erectile Dysfunction and Cardiovascular Disease: A Systematic Critical Review. Am J Mens Health 2017;11:552-63. [Crossref] [PubMed]
32. Uddin SMI, Mirbolouk M, Dardari Z, et al. Erectile Dysfunction as an Independent Predictor of Future Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis. Circulation 2018;138:540-2. [Crossref] [PubMed]
33. De Leonardis F, Colalillo G, Finazzi Agrò E, et al. Endothelial Dysfunction, Erectile Deficit and Cardiovascular Disease: An Overview of the Pathogenetic Links. Biomedicines 2022;10:1848. [Crossref] [PubMed]
34. Pober JS, Sessa WC. Inflammation and the blood microvascular system. Cold Spring Harb Perspect Biol 2014;7:a016345. [Crossref] [PubMed]
35. Zou H, Zhang X, Chen W, et al. Vascular endothelium is the basic way for stem cells to treat erectile dysfunction: a bibliometric study. Cell Death Discov 2023;9:143. [Crossref] [PubMed]
36. Cagnina A, Chabot O, Davin L, et al. Atherosclerosis, an inflammatory disease. Rev Med Liege 2022;77:302-9. [PubMed]
37. Maejima T, Inoue T, Kanki Y, et al. Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells. PLoS One 2014;9:e96005. [Crossref] [PubMed]
38. Sweet DR, Fan L, Hsieh PN, et al. Krüppel-Like Factors in Vascular Inflammation: Mechanistic Insights and Therapeutic Potential. Front Cardiovasc Med 2018;5:6. [Crossref] [PubMed]
39. Boon RA, Leyen TA, Fontijn RD, et al. KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium. Blood 2010;115:2533-42. [Crossref] [PubMed]
40. Zhang Y, Lei CQ, Hu YH, et al. Krüppel-like factor 6 is a co-activator of NF-κB that mediates p65-dependent transcription of selected downstream genes. J Biol Chem 2014;289:12876-85. [Crossref] [PubMed]
41. Zhong L, Simard MJ, Huot J. Endothelial microRNAs regulating the NF-κB pathway and cell adhesion molecules during inflammation. FASEB J 2018;32:4070-84. [Crossref] [PubMed]
42. Paudel R, Fusi L, Schmidt M. The MEK5/ERK5 Pathway in Health and Disease. Int J Mol Sci 2021;22:7594. [Crossref] [PubMed]
43. Fang C, Schmaier AH. Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems. Pharmacol Res 2020;160:105096. [Crossref] [PubMed]
44. Ku KH, Dubinsky MK, Sukumar AN, et al. In Vivo Function of Flow-Responsive Cis-DNA Elements of eNOS Gene: A Role for Chromatin-Based Mechanisms. Circulation 2021;144:365-81. [Crossref] [PubMed]
45. Wang R, Zeng Y, Chen Z, et al. Shear-Sensitive circRNA-LONP2 Promotes Endothelial Inflammation and Atherosclerosis by Targeting NRF2/HO1 Signaling. JACC Basic Transl Sci 2024;9:652-70. [Crossref] [PubMed]
46. Li S, Xu Z, Wang Y, et al. Recent advances of mechanosensitive genes in vascular endothelial cells for the formation and treatment of atherosclerosis. Genes Dis 2024;11:101046. [Crossref] [PubMed]
47. Park BH, Her SH, Han DS, et al. Erectile dysfunction and angiographic correlation between coronary artery stenosis and internal iliac-internal pudendal artery stenosis in patients with suspected coronary artery disease: a retrospective study. Journal of Men’s Health 2023;19:1-8.
48. Wang G, Li R, Feng C, et al. Galectin-3 is involved in inflammation and fibrosis in arteriogenic erectile dysfunction via the TLR4/MyD88/NF-κB pathway. Cell Death Discov 2024;10:92. [Crossref] [PubMed]
49. Shamloul R, Ghanem H. Erectile dysfunction. Lancet 2013;381:153-65. [Crossref] [PubMed]
50. Tarhan F, Kuyumcuoğlu U, Kolsuz A, et al. Cavernous oxygen tension in the patients with erectile dysfunction. Int J Impot Res 1997;9:149-53. [Crossref] [PubMed]
51. Moghimian M, Soltani M, Abtahi H, et al. Protective effect of tunica albuginea incision with tunica vaginalis flap coverage on tissue damage and oxidative stress following testicular torsion: Role of duration of ischemia. J Pediatr Urol 2016;12:390.e1-6. [Crossref] [PubMed]
52. El-Bahnasawy MS, El-Assmy A, Dawood A, et al. Effect of the use of internal iliac artery for renal transplantation on penile vascularity and erectile function: a prospective study. J Urol 2004;172:2335-9. [Crossref] [PubMed]
53. Rayt HS, Bown MJ, Lambert KV, et al. Buttock claudication and erectile dysfunction after internal iliac artery embolization in patients prior to endovascular aortic aneurysm repair. Cardiovasc Intervent Radiol 2008;31:728-34. [Crossref] [PubMed]
54. Trost LW, Munarriz R, Wang R, et al. External Mechanical Devices and Vascular Surgery for Erectile Dysfunction. J Sex Med 2016;13:1579-617. [Crossref] [PubMed]
55. Burnett AL, Nehra A, Breau RH, et al. Erectile Dysfunction: AUA Guideline. J Urol 2018;200:633-41. [Crossref] [PubMed]
56. Hatzimouratidis K, Giuliano F, Moncada I, et al. EAU guidelines on erectile dysfunction, premature ejaculation, penile curvature and priapism 2018. European Association of Urology Guidelines 2018.
57. Azadzoi KM, Goldstein I. Erectile dysfunction due to atherosclerotic vascular disease: the development of an animal model. J Urol 1992;147:1675-81. [Crossref] [PubMed]
58. Azadzoi KM, Tarcan T, Siroky MB, et al. Atherosclerosis-induced chronic ischemia causes bladder fibrosis and non-compliance in the rabbit. J Urol 1999;161:1626-35. [Crossref] [PubMed]
59. Kovanecz I, Ferrini MG, Vernet D, et al. Ageing-related corpora veno-occlusive dysfunction in the rat is ameliorated by pioglitazone. BJU Int 2007;100:867-74. [Crossref] [PubMed]
60. Nomiya M, Yamaguchi O, Andersson KE, et al. The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat. Neurourol Urodyn 2012;31:195-200. [Crossref] [PubMed]
61. Kirpatovskii VI, Mudraya IS, Mkrtchyan KG, et al. Ischemia in pelvic organs as an independent pathogenic factor in the development of benign prostatic hyperplasia and urinary bladder dysfunction. Bull Exp Biol Med 2015;158:718-22. [Crossref] [PubMed]
62. Saito M, Tsounapi P, Oikawa R, et al. Prostatic ischemia induces ventral prostatic hyperplasia in the SHR; possible mechanism of development of BPH. Sci Rep 2014;4:3822. [Crossref] [PubMed]
63. Fujimoto K, Hashimoto D, Kashimada K, et al. A visualization system for erectile vascular dynamics. Front Cell Dev Biol 2022;10:1000342. [Crossref] [PubMed]
64. Liu X, Luo P, Zhang W, et al. Roles of pyroptosis in atherosclerosis pathogenesis. Biomed Pharmacother 2023;166:115369. [Crossref] [PubMed]
65. Ye B, Fan X, Fang Z, et al. Macrophage-derived GSDMD promotes abdominal aortic aneurysm and aortic smooth muscle cells pyroptosis. Int Immunopharmacol 2024;128:111554. [Crossref] [PubMed]
66. Luo PY, Zou JR, Chen T, et al. Autophagy in erectile dysfunction: focusing on apoptosis and fibrosis. Asian J Androl 2025;27:166-76. [Crossref] [PubMed]
67. Yang CC, Liao PH, Cheng YH, et al. Diabetes associated with hypertension exacerbated oxidative stress-mediated inflammation, apoptosis and autophagy leading to erectile dysfunction in rats. J Chin Med Assoc 2022;85:346-57. [Crossref] [PubMed]
68. Vande Walle L, Lamkanfi M. Pyroptosis. Curr Biol 2016;26:R568-72. [Crossref] [PubMed]
69. Bai Y, Pan Y, Liu X. Mechanistic insights into gasdermin-mediated pyroptosis. Nat Rev Mol Cell Biol 2025;26:501-21. [Crossref] [PubMed]
70. Fu J, Schroder K, Wu H. Mechanistic insights from inflammasome structures. Nat Rev Immunol 2024;24:518-35. [Crossref] [PubMed]
71. Schiffelers LDJ, Tesfamariam YM, Jenster LM, et al. Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application. Nat Commun 2024;15:8266. [Crossref] [PubMed]
72. Burdette BE, Esparza AN, Zhu H, et al. Gasdermin D in pyroptosis. Acta Pharm Sin B 2021;11:2768-82. [Crossref] [PubMed]
73. Yu P, Zhang X, Liu N, et al. Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther 2021;6:128. [Crossref] [PubMed]
74. Li Y, Tian X, Luo J, et al. Molecular mechanisms of aging and anti-aging strategies. Cell Commun Signal 2024;22:285. [Crossref] [PubMed]
75. Shi X, Xie WL, Kong WW, et al. Expression of the NLRP3 Inflammasome in Carotid Atherosclerosis. J Stroke Cerebrovasc Dis 2015;24:2455-66. [Crossref] [PubMed]
76. Li H, Zhao Q, Liu D, et al. Cathepsin B aggravates atherosclerosis in ApoE-deficient mice by modulating vascular smooth muscle cell pyroptosis through NF-κB / NLRP3 signaling pathway. PLoS One 2024;19:e0294514. [Crossref] [PubMed]
77. Li S, Li Q, Zhou Q, et al. Attenuating Atherosclerosis through Inhibition of the NF-κB/NLRP3/IL-1β Pathway-Mediated Pyroptosis in Vascular Smooth Muscle Cells (VSMCs). Cardiovasc Ther 2024;2024:1506083. [Crossref] [PubMed]
78. Dominic A, Le NT, Takahashi M. Loop Between NLRP3 Inflammasome and Reactive Oxygen Species. Antioxid Redox Signal 2022;36:784-96. [Crossref] [PubMed]
79. Tang YS, Zhao YH, Zhong Y, et al. Neferine inhibits LPS-ATP-induced endothelial cell pyroptosis via regulation of ROS/NLRP3/Caspase-1 signaling pathway. Inflamm Res 2019;68:727-38. [Crossref] [PubMed]
80. Cao W, Li J, Yang K, et al. An overview of autophagy: Mechanism, regulation and research progress. Bull Cancer 2021;108:304-22. [Crossref] [PubMed]
81. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol 2023;24:560-75. [Crossref] [PubMed]
82. Robichaud S, Rasheed A, Pietrangelo A, et al. Autophagy Is Differentially Regulated in Leukocyte and Nonleukocyte Foam Cells During Atherosclerosis. Circ Res 2022;130:831-47. [Crossref] [PubMed]
83. Pi S, Mao L, Chen J, et al. The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. Autophagy 2021;17:980-1000. [Crossref] [PubMed]
84. Basatemur GL, Jørgensen HF, Clarke MCH, et al. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 2019;16:727-44. [Crossref] [PubMed]
85. Border WA, Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest 1992;90:1-7. [Crossref] [PubMed]
86. Grootaert MOJ, Moulis M, Roth L, et al. Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis. Cardiovasc Res 2018;114:622-34. [Crossref] [PubMed]
87. Chueh KS, Lu JH, Juan TJ, et al. The Molecular Mechanism and Therapeutic Application of Autophagy for Urological Disease. Int J Mol Sci 2023;24:14887. [Crossref] [PubMed]
88. Budi EH, Schaub JR, Decaris M, et al. TGF-β as a driver of fibrosis: physiological roles and therapeutic opportunities. J Pathol 2021;254:358-73. [Crossref] [PubMed]
89. Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol 2016;12:325-38. [Crossref] [PubMed]
90. Ruiz-Ortega M, Rodríguez-Vita J, Sanchez-Lopez E, et al. TGF-beta signaling in vascular fibrosis. Cardiovasc Res 2007;74:196-206. [Crossref] [PubMed]
91. Lee JH, Massagué J. TGF-β in developmental and fibrogenic EMTs. Semin Cancer Biol 2022;86:136-45. [Crossref] [PubMed]
92. Peng D, Fu M, Wang M, et al. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer 2022;21:104. [Crossref] [PubMed]
93. Grainger DJ. TGF-beta and atherosclerosis in man. Cardiovasc Res 2007;74:213-22. [Crossref] [PubMed]
94. Chen PY, Qin L, Li G, et al. Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis. Nat Metab 2019;1:912-26. [Crossref] [PubMed]
95. Di XP, Jin X, Ai JZ, et al. YAP/Smad3 promotes pathological extracellular matrix microenviroment-induced bladder smooth muscle proliferation in bladder fibrosis progression. MedComm (2020) 2022;3:e169.
96. Edsfeldt A, Singh P, Matthes F, et al. Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events. Cardiovasc Res 2023;119:2061-73. [Crossref] [PubMed]
97. Bakalenko N, Kuznetsova E, Malashicheva A. The Complex Interplay of TGF-β and Notch Signaling in the Pathogenesis of Fibrosis. Int J Mol Sci 2024;25:10803. [Crossref] [PubMed]
98. Khalifa MO, Yan C, Chai Y, et al. Hydrostatic pressure mediates epithelial-mesenchymal transition of cholangiocytes through RhoA/ROCK and TGF-β/smad pathways. PLoS One 2024;19:e0300548. [Crossref] [PubMed]
99. Lu C, Sidoli S, Kulej K, et al. Coordination between TGF-β cellular signaling and epigenetic regulation during epithelial to mesenchymal transition. Epigenetics Chromatin 2019;12:11. [Crossref] [PubMed]
100. Aashaq S, Batool A, Mir SA, et al. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol 2022;237:59-85. [Crossref] [PubMed]
101. Yu XY, Sun Q, Zhang YM, et al. TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis. Front Pharmacol 2022;13:860588. [Crossref] [PubMed]
102. Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci 2005;118:3573-84. [Crossref] [PubMed]
103. Zhang YE. Non-Smad Signaling Pathways of the TGF-β Family. Cold Spring Harb Perspect Biol 2017;9:a022129. [Crossref] [PubMed]
104. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-84. [Crossref] [PubMed]
105. Du L, Zhu W. Research progress on TGF-β gene family. Oct Jour Env Res 2024;12:001-010..
106. Hu Y, He J, He L, et al. Expression and function of Smad7 in autoimmune and inflammatory diseases. J Mol Med (Berl) 2021;99:1209-20. [Crossref] [PubMed]
107. Chen D, Tang H, Jiang H, et al. ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation. Front Pharmacol 2022;13:835979. [Crossref] [PubMed]
108. Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich) 2006;8:53-62. [Crossref] [PubMed]
109. Nehra A, Nugent M, Pabby A, et al. An in vivo model for transforming growth factor-β1 induced corporal fibrosis: implications for penile ischemia-associated fibrosis. J Urol 1996;155:622A.
110. Mazuryk O, Gurgul I, Oszajca M, et al. Nitric Oxide Signaling and Sensing in Age-Related Diseases. Antioxidants (Basel) 2024;13:1213. [Crossref] [PubMed]
111. Sharina I, Martin E. Cellular Factors That Shape the Activity or Function of Nitric Oxide-Stimulated Soluble Guanylyl Cyclase. Cells 2023;12:471. [Crossref] [PubMed]
112. Kamel R, Leroy J, Vandecasteele G, et al. Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. Nat Rev Cardiol 2023;20:90-108. [Crossref] [PubMed]
113. Degjoni A, Campolo F, Stefanini L, et al. The NO/cGMP/PKG pathway in platelets: The therapeutic potential of PDE5 inhibitors in platelet disorders. J Thromb Haemost 2022;20:2465-74. [Crossref] [PubMed]
114. Sullivan CJ, Teal TH, Luttrell IP, et al. Microarray analysis reveals novel gene expression changes associated with erectile dysfunction in diabetic rats. Physiol Genomics 2005;23:192-205. [Crossref] [PubMed]
115. Gonzalez-Cadavid NF, Rajfer J. The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra's advent. A personal perspective. Int J Impot Res 2019;31:57-60. [Crossref] [PubMed]
116. Morelli A, Vignozzi L, Filippi S, et al. Erectile dysfunction: molecular biology, pathophysiology and pharmacological treatment. Minerva Urol Nefrol 2005;57:85-90. [PubMed]
117. Wang G, Shen D, Zhang X, et al. Comparison of critical biomarkers in 2 erectile dysfunction models based on GEO and NOS-cGMP-PDE5 pathway. Medicine (Baltimore) 2021;100:e27508. [Crossref] [PubMed]
118. Andersson KE. PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol 2018;175:2554-65. [Crossref] [PubMed]
119. Musicki B, Lagoda G, Goetz T, et al. Transnitrosylation: A Factor in Nitric Oxide-Mediated Penile Erection. J Sex Med 2016;13:808-14. [Crossref] [PubMed]
120. Ghalayini IF. Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. Int J Impot Res 2004;16:459-69. [Crossref] [PubMed]
121. Maseroli E, Vignozzi L. Testosterone and Vaginal Function. Sex Med Rev 2020;8:379-92. [Crossref] [PubMed]
122. Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation 2004;109:II27-33. [Crossref] [PubMed]
123. Domanski MJ, Tian X, Wu CO, et al. Time Course of LDL Cholesterol Exposure and Cardiovascular Disease Event Risk. J Am Coll Cardiol 2020;76:1507-16. [Crossref] [PubMed]
124. Rabelink TJ, Luscher TF. Endothelial nitric oxide synthase: host defense enzyme of the endothelium? Arterioscler Thromb Vasc Biol 2006;26:267-71. [Crossref] [PubMed]
125. Eardley I. The Incidence, Prevalence, and Natural History of Erectile Dysfunction. Sex Med Rev 2013;1:3-16. [Crossref] [PubMed]
126. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61. [Crossref] [PubMed]
127. Braun M, Wassmer G, Klotz T, et al. Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey'. Int J Impot Res 2000;12:305-11. [Crossref] [PubMed]
128. Schouten BW, Bosch JL, Bernsen RM, et al. Incidence rates of erectile dysfunction in the Dutch general population. Effects of definition, clinical relevance and duration of follow-up in the Krimpen Study. Int J Impot Res 2005;17:58-62. [Crossref] [PubMed]
129. Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000;163:460-3. [Crossref] [PubMed]
130. Capogrosso P, Colicchia M, Ventimiglia E, et al. One patient out of four with newly diagnosed erectile dysfunction is a young man--worrisome picture from the everyday clinical practice. J Sex Med 2013;10:1833-41. [Crossref] [PubMed]
131. Brannigan RE, Hermanson L, Kaczmarek J, et al. Updates to Male Infertility: AUA/ASRM Guideline (2024). J Urol 2024;212:789-99. [Crossref] [PubMed]
132. Kessler A, Sollie S, Challacombe B, et al. The global prevalence of erectile dysfunction: a review. BJU Int 2019;124:587-99. [Crossref] [PubMed]
133. Nguyen HMT, Gabrielson AT, Hellstrom WJG. Erectile Dysfunction in Young Men-A Review of the Prevalence and Risk Factors. Sex Med Rev 2017;5:508-20. [Crossref] [PubMed]
134. Goldstein I, Goren A, Li VW, et al. Epidemiology Update of Erectile Dysfunction in Eight Countries with High Burden. Sex Med Rev 2020;8:48-58. [Crossref] [PubMed]
135. Ziapour A, Kazeminia M, Rouzbahani M, et al. Global prevalence of sexual dysfunction in cardiovascular patients: a systematic review and meta-analysis. Syst Rev 2024;13:136. [Crossref] [PubMed]
136. Irfan M, Hussain NHN, Noor NM, et al. Epidemiology of Male Sexual Dysfunction in Asian and European Regions: A Systematic Review. Am J Mens Health 2020;14:1557988320937200. [Crossref] [PubMed]
137. Frühauf S, Gerger H, Schmidt HM, et al. Efficacy of psychological interventions for sexual dysfunction: a systematic review and meta-analysis. Arch Sex Behav 2013;42:915-33. [Crossref] [PubMed]
138. Gupta BP, Murad MH, Clifton MM, et al. The effect of lifestyle modification and cardiovascular risk factor reduction on erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2011;171:1797-803. [Crossref] [PubMed]
139. Hatzimouratidis K, Salonia A, Adaikan G, et al. Pharmacotherapy for Erectile Dysfunction: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med 2016;13:465-88. [Crossref] [PubMed]
140. Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1:6-23. [Crossref] [PubMed]
141. Allen MS. Physical activity as an adjunct treatment for erectile dysfunction. Nat Rev Urol 2019;16:553-62. [Crossref] [PubMed]
142. Baumhäkel M, Schlimmer N, Kratz M, et al. Cardiovascular risk, drugs and erectile function--a systematic analysis. Int J Clin Pract 2011;65:289-98. [Crossref] [PubMed]
143. Glina S, Sharlip ID, Hellstrom WJ. Modifying risk factors to prevent and treat erectile dysfunction. J Sex Med 2013;10:115-9. [Crossref] [PubMed]
144. Yuan J, Zhang R, Yang Z, et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. Eur Urol 2013;63:902-12. [Crossref] [PubMed]
145. Capogrosso P, Frey A, Jensen CFS, et al. Low-Intensity Shock Wave Therapy in Sexual Medicine-Clinical Recommendations from the European Society of Sexual Medicine (ESSM). J Sex Med 2019;16:1490-505. [Crossref] [PubMed]
146. Chung E, Cartmill R. Evaluation of clinical efficacy, safety and patient satisfaction rate after low-intensity extracorporeal shockwave therapy for the treatment of male erectile dysfunction: an Australian first open-label single-arm prospective clinical trial. BJU Int 2015;115:46-49. [Crossref] [PubMed]
147. Gruenwald I, Appel B, Vardi Y. Low-intensity extracorporeal shock wave therapy--a novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. J Sex Med 2012;9:259-64. [Crossref] [PubMed]
148. Omari M, Alkhalil M. Atherosclerosis Residual Lipid Risk-Overview of Existing and Future Pharmacotherapies. J Cardiovasc Dev Dis 2024;11:126. [Crossref] [PubMed]
149. Anastasiadis E, Ahmed R, Khoja AK, et al. Erectile dysfunction: Is platelet-rich plasma the new frontier for treatment in patients with erectile dysfunction? A review of the existing evidence. Front Reprod Health 2022;4:944765. [Crossref] [PubMed]
150. Figueiredo CS, Roseira ES, Viana TT, et al. Inflammation in Coronary Atherosclerosis: Insights into Pathogenesis and Therapeutic Potential of Anti-Inflammatory Drugs. Pharmaceuticals (Basel) 2023;16:1242. [Crossref] [PubMed]
151. Mao Q, Yang Y, Liu Y, et al. The efficacy of platelet rich plasma in the treatment of erectile dysfunction: a systematic review and meta-analysis of randomized controlled trials. Aging Male 2024;27:2358944. [Crossref] [PubMed]
152. Masterson TA, Molina M, Ledesma B, et al. Platelet-rich Plasma for the Treatment of Erectile Dysfunction: A Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial. J Urol 2023;210:154-61. [Crossref] [PubMed]
153. Poulios E, Mykoniatis I, Pyrgidis N, et al. Platelet-rich plasma for the treatment of erectile dysfunction: a systematic review of preclinical and clinical studies. Sex Med Rev 2023;11:359-68. [Crossref] [PubMed]
154. Shaher H, Fathi A, Elbashir S, et al. Is Platelet Rich Plasma Safe and Effective in Treatment of Erectile Dysfunction? Randomized Controlled Study. Urology 2023;175:114-9. [Crossref] [PubMed]
155. Levine LA, Dimitriou RJ. Vacuum constriction and external erection devices in erectile dysfunction. Urol Clin North Am 2001;28:335-41. ix-x. [Crossref] [PubMed]
156. Yuan J, Hoang AN, Romero CA, et al. Vacuum therapy in erectile dysfunction--science and clinical evidence. Int J Impot Res 2010;22:211-9. [Crossref] [PubMed]
157. Eardley I, Donatucci C, Corbin J, et al. Pharmacotherapy for erectile dysfunction. J Sex Med 2010;7:524-40. [Crossref] [PubMed]
158. Porst H, Burnett A, Brock G, et al. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J Sex Med 2013;10:130-71. [Crossref] [PubMed]
159. Saad F, Caliber M, Doros G, et al. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. Aging Male 2020;23:81-92. [Crossref] [PubMed]
160. Taniguchi H, Shimada S, Kinoshita H. Testosterone Therapy for Late-Onset Hypogonadism Improves Erectile Function: A Systematic Review and Meta-Analysis. Urol Int 2022;106:539-52. [Crossref] [PubMed]
161. Antonini G, Busetto GM, De Berardinis E, et al. Minimally invasive infrapubic inflatable penile prosthesis implant for erectile dysfunction: evaluation of efficacy, satisfaction profile and complications. Int J Impot Res 2016;28:4-8. [Crossref] [PubMed]
162. Hellstrom WJ, Montague DK, Moncada I, et al. Implants, mechanical devices, and vascular surgery for erectile dysfunction. J Sex Med 2010;7:501-23. [Crossref] [PubMed]
163. Martínez-Salamanca JI, Mueller A, Moncada I, et al. Penile prosthesis surgery in patients with corporal fibrosis: a state of the art review. J Sex Med 2011;8:1880-9. [Crossref] [PubMed]
164. Montague DK. Penile prosthesis implantation in the era of medical treatment for erectile dysfunction. Urol Clin North Am 2011;38:217-25. [Crossref] [PubMed]
165. Lu Y, Cui X, Zhang L, et al. The Functional Role of Lipoproteins in Atherosclerosis: Novel Directions for Diagnosis and Targeting Therapy. Aging Dis 2022;13:491-520. [Crossref] [PubMed]
166. Soleimani H, Mousavi A, Shojaei S, et al. Safety and Effectiveness of High-Intensity Statins Versus Low/Moderate-Intensity Statins Plus Ezetimibe in Patients With Atherosclerotic Cardiovascular Disease for Reaching LDL-C Goals: A Systematic Review and Meta-Analysis. Clin Cardiol 2024;47:e24334. [Crossref] [PubMed]
167. Deng X, Wang J, Yu S, et al. editors. Advances in the treatment of atherosclerosis with ligand-modified nanocarriers. Wiley Online Library; 2024.
168. Li M, Wang Z, Wang P, et al. TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis. Front Physiol 2021;12:639920. [Crossref] [PubMed]
169. Lin Y, Lin R, Lin H-B, et al. Nanomedicine-based drug delivery strategies for the treatment of atherosclerosis. Medicine in Drug Discovery 2024;22:100189. [Crossref]
170. Raheem OA, Natale C, Dick B, et al. Novel Treatments of Erectile Dysfunction: Review of the Current Literature. Sex Med Rev 2021;9:123-32. [Crossref] [PubMed]
171. Yang B, Zhong W, Gu Y, et al. Emerging Mechanisms and Targeted Therapy of Pyroptosis in Central Nervous System Trauma. Front Cell Dev Biol 2022;10:832114. [Crossref] [PubMed]
172. Bakhshi S, Shamsi S. MCC950 in the treatment of NLRP3-mediated inflammatory diseases: Latest evidence and therapeutic outcomes. Int Immunopharmacol 2022;106:108595. [Crossref] [PubMed]
173. Li H, Guan Y, Liang B, et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. Eur J Pharmacol 2022;928:175091. [Crossref] [PubMed]
174. Zheng Y, Zhang X, Wang Z, et al. MCC950 as a promising candidate for blocking NLRP3 inflammasome activation: A review of preclinical research and future directions. Arch Pharm (Weinheim) 2024;357:e2400459. [Crossref] [PubMed]
175. Kikuchi S, Kayama K, Kawada Y, et al. Evaluation of renal circulation in heart failure using superb microvascular imaging, a microvascular flow imaging system. J Med Ultrason (2001) 2024;51:283-92. [Crossref] [PubMed]
176. Tang K, Liu M, Zhu Y, et al. The clinical application of ultrasonography with superb microvascular imaging-a review. J Clin Ultrasound 2022;50:721-32. [Crossref] [PubMed]
177. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387-97. [Crossref] [PubMed]