Vascular aging-driven erectile dysfunction: pathophysiological mechanisms and emerging therapies—a narrative review

Introduction

Background and objective

Erectile dysfunction (ED) is characterized by the persistent inability to achieve and/or maintain a penile erection sufficient for satisfactory sexual intercourse (1). Penile erection is a neurovascular process that is influenced by psychological factors (2). Erections can be categorized as central, reflexogenic, or nocturnal. Central erections begin with a stimulus from supraspinal centers that travels through the spinal cord and reaches the corpora cavernosa via the cavernous nerves. Reflexogenic erection is mainly induced by direct physical stimulation of the penis or adjacent erogenous zones (3). Neurotransmitters released by the terminal branches of the cavernous nerves, including nitric oxide (NO), vasoactive intestinal polypeptide, acetylcholine, and prostaglandins, play a key role in initiating the erectile process. Endothelial cells in the cavernous sinusoids, stimulated by shear stress, release active mediators that contribute to smooth muscle relaxation in the penile arteries and sinusoids (4). This relaxation results in the filling of the corpora cavernosa with blood, leading to compression of the subalbugineal venular plexus against the tunica albuginea. Activation of the veno-occlusive mechanism traps blood within the corpora cavernosa, creating an isovolumetric reservoir (5). Further arterial inflow increases intracorporeal pressure, resulting in penile rigidity, a process dependent on the full relaxation of vascular smooth muscle cells (VSMCs) in the penile arteries and cavernous sinusoids (6). In the erection process, the corpus cavernosum muscle and ischiocavernosus muscle (ICM) act synergistically to enable and sustain erection. As the core smooth muscle of the corpus cavernosum, the corpus cavernosum muscle relaxes upon sexual stimulation (e.g., reflexive or psychological), expanding the internal vascular spaces (sinusoids) and reducing vascular resistance to accelerate arterial blood inflow, laying the foundation for penile engorgement (7-9). The ICM is a paired, short, pinnate striated muscle attached to the pelvic ring. It originates from the ischial tuberosity and covers the crus of the penis, ending at the crus itself. The ICM plays a critical auxiliary role in achieving and maintaining penile rigidity (10). During erection, the contraction of the ICM compresses the crura of the penis against the pubic bone, which further elevates intracavernous pressure to suprasystolic levels (11). This compression restricts venous outflow, effectively preventing blood from leaving the corpora cavernosa and thus enhancing penile rigidity.

In epidemiological studies, an association between aging and male ED has been identified (12). The aging process can impact various aspects of the erectile process, such as nerves, arteries, veins, cavernous tissue, and hormones, leading to vascular and endocrinological abnormalities playing a significant role in male ED (13). Among them, abnormalities related to blood vessels are particularly critical in aging-induced ED—the process of vascular changes during human aging and the occurrence of atherosclerosis in other parts of the body will also affect erectile function (14). Studies have indicated that penile atherosclerosis is one of the most common causes of ED (15). Based on this, this review first analyzes the characteristics of vascular endothelial and smooth muscle changes in elderly ED patients, then explores the pathophysiological association between cardiovascular disease (CVD) and ED in elderly men, and further introduces a new perspective on the diagnosis and treatment of age-related ED, aiming to help clinicians understand the underlying pathophysiological mechanisms of ED. And these cognitions were applied to actual patient management. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-581/rc).

Methods

This review focuses on studies related to vascular ED associated with aging between 2000 and 2025, covering human and preclinical animal experiments. Relevant literatures were screened by searching databases such as PubMed, Web of Science, and Embase using keywords including “erectile dysfunction”, “aging”, “vascular endothelium”, and “vascular smooth muscle”. The inclusion criteria are as follows: the research subjects are humans or animal models; the research content involves the pathophysiological mechanisms between vascular aging and ED, emerging therapeutic methods, etc.; the literature language is English or Chinese. The exclusion criteria include duplicate publications, non-peer-reviewed literatures, and studies irrelevant to the theme. During the screening process, high-quality clinical studies and innovative experimental studies were prioritized to ensure the scientificity and practicality of the review content (Table 1).

Discussion

Pathophysiology of vascular aging in ED

Penile erection is a complex neurovascular phenomenon that involves the coordination of three hemodynamic events: increased arterial inflow, sinusoidal smooth muscle relaxation, and decreased venous outflow (16). Any alteration in these components can impact the response of the erectile tissue, leading to ED. Both coronary artery disease (CAD) and ED are highly prevalent conditions that often coexist. ED and CVD share common cardiovascular risk factors and pathophysiological pathways (17). Vascular risk factors, such as diabetes and hypercholesterolemia, can disrupt the histology of penile erectile tissue, resulting in corporal veno-occlusive dysfunction (18). Atherosclerosis-induced ED (AED) is a common and clinically significant vascular disorder that affects men’s quality of life and serves as a potential early indicator of systemic CVD (19). The complex vasculature supplying the penis is particularly vulnerable to injury due to regional factors, making it more susceptible than other vascular beds (20).

Several mechanisms have been proposed to explain the association between ED and CVD. One of these is known as the “artery size hypothesis” (21). Atherosclerosis affects all major vascular beds to a similar extent, but the penile arteries have a smaller diameter than the coronary arteries (1–2 vs. 3–4 mm), making them more susceptible to early accumulation of atherosclerotic plaque (22). This can lead to the onset of ED occurring before vascular events in the heart. Another possible explanation is that endothelial dysfunction may serve as a shared etiologic factor for both conditions (23). Dysfunction in the endothelium is an early indicator of the development of atherosclerotic changes and may also contribute to the incidence of acute cardiovascular events (24).

Age is a significant risk factor for CVD, such as atherosclerosis. The influence of age on cardiovascular risk is attributed to the progressive nature of CVD processes or the accumulation of cardiovascular risk factors over time (25). The understanding of the connection between CAD and age has advanced to recognize the interplay of atherosclerotic plaque formation with the pathophysiological characteristics of vascular aging, which are accelerated by traditional risk factors for atherosclerosis (26). Key age-related characteristics, including endothelial dysfunction, arterial stiffening, and intimal thickening, form the basis for the subsequent development of atherosclerosis, with age also influencing the composition of plaque. While these traits are typical of vascular aging, not all individuals exhibiting them will develop CAD. Nevertheless, there have been limited efforts to identify the conditions under which these characteristics constitute normal or healthy vascular aging, and when they increase vulnerability to the development of CAD and associated adverse events. Arteriogenic ED is closely linked to these age-related vascular changes. Understanding these processes is crucial for identifying ED as an early indicator of CVD.

Endothelium and NO/endothelial NO synthase (eNOS)

Erectile function is a complex physiological process that requires the synergistic action of multiple systems such as nerves, blood vessels, and endocrine (Figure 1). As a key component of the inner wall of blood vessels, the dysfunction of vascular endothelial cells not only affects cardiovascular health, but also significantly impairs penile erectile function (27). Normal penile erection depends on adequate blood filling of the corpus cavernosus, which is closely related to the precise regulation of endothelial cells through the process of “endothelial function → NO production → smooth muscle relaxation”. Specifically, endothelial cells release vasoactive substances such as NO, which is the central signaling molecule during erection and is catalyzed by eNOS in endothelial cells (28). NO can promote relaxation of corpus cavernosum smooth muscle and vasodilation, thereby increasing penile blood flow and ultimately promoting erection (29). However, the function of this axis is impaired with age: as individuals age, vascular endothelial cells will show increased oxidative stress and inflammatory response, which will directly lead to decreased bioavailability of NO, and then break the normal pathway of “endothelial function → NO production → smooth muscle relaxation → blood flow filling”, affecting erectile function (30).

Figure 1 Molecular mechanisms of vascular age-related erectile dysfunction. This schematic contrasts molecular pathways governing penile erection in young versus aged vascular tissues. In the young state (left), ECs convert L-arginine to NO via eNOS, stimulated by ACh; NO diffuses to SMCs, activating sGC to generate cGMP from GTP, promoting SMC relaxation, vasodilation, and erection, while PDE5 degrades cGMP to terminate signaling. Ca²⁺ homeostasis and endoplasmic reticulum function support normal tone. In the aged state (right), ROS, inflammation (elevated IL-6, TNF-α, ICAM-1, VCAM-1), testosterone deficiency, and eNOS uncoupling cause endothelial DNA damage and apoptosis, reducing NO bioavailability. Concurrently, SMCs exhibit TGF-β1 overexpression, PGE1 reduction, and disrupted cGMP signaling (cGMP↓), leading to fibrosis, Ca²⁺ dysregulation, endoplasmic reticulum stress, and failed relaxation, collectively driving erectile dysfunction through vascular inflammation, structural remodeling, and impaired vasodilatory pathways. ACh, acetylcholine; Ca²⁺, calcium; cGMP, cyclic guanosine monophosphate; ECs, endothelial cells; eNOS, endothelial NO synthase; GC, guanylate cyclase; GTP, guanosine triphosphate; ICAM-1, intercellular adhesion molecule-1; IL-6, interleukin-6; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; PDE5, phosphodiesterase-5; PGE1, prostaglandin E1; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; SMCs, smooth muscle cells; TGF-β1, transforming growth factor beta 1; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1.

Oxidative stress is a significant contributor to endothelial cell dysfunction. In normal circumstances, the body’s production of reactive oxygen species (ROS) is balanced by the antioxidant system. However, certain conditions such as hypertension, diabetes, and smoking can disrupt this balance, causing an increase in ROS production that overwhelms the antioxidant system, resulting in oxidative stress (31). Oxidative stress reduces NO production through the “endothelial function → NO production → smooth muscle relaxation” mentioned above. In addition, it can trigger endothelial cell apoptosis and inflammatory responses. Hyperglycemia and oxidative stress in diabetes can lead to vascular damage and a decrease in blood flow to the corpus cavernosum (32). Moreover, hyperglycemia and advanced glycation end products can exacerbate oxidative stress, leading to the generation of superoxide free radicals and activating various pathways that ultimately contribute to endothelial cell injury and apoptosis. These mechanisms can cause a decrease in eNOS and vascular endothelial growth factor (VEGF) synthesis, with eNOS playing a role in the NO/cyclic guanosine monophosphate (cGMP) pathway and VEGF serving as a crucial factor for promoting angiogenesis and endothelial proliferation, thereby enhancing penile blood flow (33). Furthermore, diabetic patients experience inhibition of the differentiation and regulatory functions of endothelial progenitor cells, which further impairs vascular endothelial function (34).

Chronic inflammation is a prevalent factor in causing dysfunction of endothelial cells (35). Aging endothelial cells release higher levels of pro-inflammatory cytokines, cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (36). As well as adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) leading to the adherence and migration of leukocytes, triggering chronic inflammation that damages the endothelium (37). This damage inhibits the expression and function of eNOS, reducing the release of NO. Moreover, inflammation can stimulate the proliferation and migration of VSMCs, resulting in thickening and narrowing of the blood vessel wall, affecting blood flow to the penis. Endothelial cell dysfunction can augment the production of vasoconstrictors like endothelin-1 (ET-1), exacerbating vascular constriction and reducing blood flow to the penis. Endocrine disorders can also impact endothelial cell function, as seen in the decrease in androgen levels leading to diminished endothelial cell function and NO production (38). Insulin resistance and hyperglycemia, common in diabetic patients, can harm endothelial cells and erectile function.

There exists a significant relationship between endothelial cells and the aging process. With increasing age, endothelial cells experience a range of structural and functional modifications, including imbalances in vascular tone, enhanced endothelial permeability, development of atherosclerosis, compromised vasculogenesis and repair capabilities, and decreased mitochondrial biosynthesis in endothelial cells (39). Mitochondrial reactive oxygen species (mtROS) have been involved in the vascular complications of metabolic disorders. Wistar rats were fed a high-fat diet (HFD) or standard diet (STD), and penile vascular function was assessed in microvascular myographs. This study clarified the mechanism underlying the effect of diet-induced obesity on penile vascular function: in penile arteries of obese rats, the level of mtROS was significantly increased, which was associated with the upregulation of NADPH oxidase 4 (Nox4) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Meanwhile, there were impairments in endothelium-dependent relaxation (decreased relaxant response to acetylcholine), reduction in mitochondrial bioenergetics (respiratory dysfunction), and dysfunction of mitochondrial ATP-sensitive potassium (mitoKATP) channel-mediated relaxation—the latter may be related to mitochondrial dysfunction and mtROS production. Although mitochondrial-derived H₂O₂ enhances vasodilation in obesity as a compensatory mechanism, obesity still induces penile vascular dysfunction through the aforementioned pathological changes (40). These alterations involve disruptions at various levels, such as disturbances in the cell cycle, oxidative stress, abnormal calcium signaling, hyperuricemia, vascular inflammation, and changes in different cellular pathways (41). Consequently, it is essential to view ED and CVD as distinct yet interconnected manifestations of the same underlying systemic disorder, with a common etiological factor being endothelial dysfunction.

Smooth muscle cell (SMC)/veno-occlusion and fibrosis

Normal penile erection occurs when the smooth muscle of the corpus cavernosum relaxes and venous return decreases, allowing blood to be trapped within the corpus cavernosum. This process relies on the integrity of the tunica surrounding the corpus cavernosum, particularly the complete relaxation of smooth muscle fibers responsible for the mechanism of vein occlusion, specifically the smooth muscle in the corpora cavernosa and the media of the penile arteries (42). In many cases, ED is linked to primary alterations in the smooth muscles of the corpus cavernosum, as their tone regulates the stages of erection. The increase in blood flow through arterial vessels and the enlargement of corporal sinusoids result from the relaxation of smooth muscle in both the arterial vessels and corporal sinusoids (43). This relaxation is controlled by the release of NO synthesized by the neuronal nitric oxide synthase (nNOS), located outside the SMCs in the terminal axons of the nerve innervating the corporal smooth muscle (44). The NO produced by nNOS quickly enters the SMCs, initiating the process of smooth muscle relaxation.

A study assessed the percentage of SMCs in a cohort of patients across different age groups exhibiting normal erectile function. A total sample of 89 tissues from different male cadavers was analyzed. The average age of the sample was 49.2±19.1 years, with a range between 14 and 90 years. The study found a statistically significant inverse correlation between age and the percentage of smooth muscle content, a statistically significant positive correlation between age and the percentage of collagen content, and an inverse correlation between age and smooth muscle (related index) collagen content. These age-related morphological changes in the human corpus cavernosum may act as a contributing factor to the development of ED (45). The ability of penile corporal veno-occlusive function relies on the elastic and expansible cavernosal tissues’ ability to generate adequate compressive and stretching forces on subtunical draining venules to induce venous outflow resistance (46). The crucial determinant for achieving normal penile corporal veno-occlusion appears to be the percentage of corporal smooth muscle content, as opposed to the quantity of elastic fibers or endothelial cells, which do not show a significant correlation with the issue of venous leakage. Studies have noted a link between the severity of penile ED and changes in cavernosal smooth muscle content, with erectile flow rates in patients with veno-occlusive dysfunction being found to correlate with the percentage of cavernosal smooth muscle content (47).

Atherosclerosis contributes to the development and progression of ED by reducing arterial blood supply to the corpus cavernosum, impairing vascular endothelial function, and disrupting the mechanism of venous occlusion (48). The severity of arterial occlusion has been correlated with a reduced proportion of smooth muscle in the corpus cavernosum. It is likely that hypoxia-induced over-expression of transforming growth factor beta 1 (TGF-β1) plays a key role in the process of ischemia-induced damage. TGF-β1 is a pleiotropic cytokine that mediates tissue fibrosis. Its overproduction decreases the smooth muscle to connective tissue ratio by inducing collagen, fibronectin, and proteoglycans expression while inhibiting SMCs growth and collagenase activity (49). Cavernosal oxygen tension also appears to regulate prostanoid production in the corpus cavernosum, as low oxygen tension decreases basal and stimulated production of prostacyclin (PGI2), thromboxane A2, prostaglandin F2 alpha and prostaglandin E2. Lower levels of prostaglandin E1 (PGE1) are correlated with increased expression of TGF-β1 mRNA in human corpus cavernosum SMCs, suggesting a potential role of low oxygen tension in ischemia-induced cavernosal fibrosis. Additionally, oxygen tension plays an important role in regulating NO synthesis, which is a major neurotransmitter in erection. Consequently, low oxygen tension may contribute to the decreased relaxation of smooth muscle fibers (50).

Arterial stiffness and inflow limitation

The pathological link between arterial stiffness and age-related ED stems from the unique vulnerability of penile vasculature to aging processes, where ED often manifests earlier than systemic vascular diseases, a phenomenon attributed to the penis serving as a “sentinel” organ for vascular health (51). Central to this process is the progressive loss of arterial compliance, driven by collagen accumulation, elastic fiber degradation, and VSMC senescence, which are particularly pronounced in cavernosal arteries (52). These structural alterations are compounded by oxidative stress and chronic inflammation, further impairing endothelial function and reducing NO bioavailability. Clinically, arterial stiffness, quantified by pulse wave analysis metrics like augmentation index, strongly correlates with ED severity, while hemodynamic studies reveal parallel declines in flow-mediated dilation (FMD) and erectile function (53).

Metabolic disorders such as diabetes and hypertension accelerate this vicious cycle by promoting glycocalyx damage and VSMC dysfunction. Endothelial dysfunction plays a key role in the initiation of cellular events evolving into the development of vascular complications in diabetes and hypertension (54). Interventions targeting arterial stiffness—including aerobic exercise and exploratory approaches such as Klotho-based strategies—show potential in early studies, but clinical validation in ED is limited. for ED management. Additionally, H2S signaling via the Foxm1 pathway attenuates VSMC senescence, while SGLT2 inhibitors reduce oxidative stress markers in aged vasculature. These findings position arterial stiffness not only as a pathological cornerstone of ED but also as a modifiable target for early intervention, with lifestyle and pharmacological strategies offering dual benefits for vascular and erectile health (55).

Systemic inflammation-oxidative stress-hormonal axis

The interplay between chronic inflammation and oxidative stress leads to age-related ED by affecting the “axis of endothelial function → NO production → smooth muscle relaxation”. In the aged vasculature, a persistent inflammatory state amplifies ROS production, leading to mitochondrial damage and phenotypic changes in endothelial cells (56). The penile vasculature demonstrates particular vulnerability to these age-related changes, often manifesting ED before systemic vascular disease becomes clinically apparent, positioning ED as an early sentinel of vascular aging.

Molecular mechanisms underlying this pathology involve nicotinamide adenine dinucleotide (NAD+) depletion through CD38 activation, which exacerbates age-related cellular dysfunction, while telomere attrition promotes senescence-associated secretory phenotype (SASP) that further fuels vascular inflammation (57). Mitochondrial dysfunction serves as both source and consequence of oxidative stress, generating excessive ROS that disrupt cellular lipid metabolism and impair vascular function. Concurrent downregulation of the Nrf2 antioxidant system leaves vasculature defenseless against oxidative damage, a phenomenon particularly pronounced in diabetic ED. Clinically, these processes manifest through elevated proinflammatory cytokines (TNF-α, IL-6, IL-8) in ED patients, with TNF-α directly impairing erectile function by amplifying oxidative stress. These inflammatory markers correlate strongly with metabolic syndrome parameters, collectively forming predictive biomarkers for ED severity (58).

Emerging evidence suggests multi-organ crosstalk, such as gut microbiome dysbiosis, may accelerate these processes through systemic inflammatory signaling (59). Therapeutic strategies targeting these mechanisms, including Nrf2 activation, mitochondrial protection, and anti-inflammatory interventions, hold promise for mitigating age-related ED while potentially addressing broader vascular aging processes. This integrated understanding positions chronic inflammation and oxidative stress not merely as biomarkers but as central, modifiable drivers of ED pathogenesis in aging males.

Hormonal imbalances and metabolic disruption

The intricate relationship between hormonal dysregulation and age-related ED is characterized by multifaceted pathophysiological interactions (60). Central to this association is the age-related decline in testosterone levels, resulting from diminished hypothalamic-pituitary-testicular axis function, including reduced GnRH secretion and impaired Leydig cell responsiveness to luteinizing hormone (LH) stimulation (61). This late-onset hypogonadism (LOH) is not only a marker of male aging, but also directly involved in the pathogenesis of ED by aggravating oxidative stress in penile tissues and leading to endothelial dysfunction and vascular damage by affecting the “endothelial function → NO production → smooth muscle relaxation axis” (62). The hormonal perturbations extend beyond testosterone deficiency, encompassing alterations in FSH, LH, and sex hormone-binding globulin (SHBG) levels (63), as well as vitamin D deficiency (64), which has been implicated in ED development through specific molecular pathways involving superoxide dysregulation.

The resultant oxidative stress from testosterone deficiency creates a permissive environment for ED progression, with evidence suggesting that antioxidants like resveratrol may partially restore erectile function by mitigating TNF-α-mediated damage (65). Notably, aging renders penile vasculature particularly susceptible to oxidative injury, amplifying the impact of hormonal imbalances. Clinical observations underscore these mechanisms, demonstrating significant correlations between low testosterone levels and ED in liver disease patients, independent of β-blocker therapy, while androgen deprivation therapy in prostate cancer patients frequently induces refractory ED, highlighting the therapeutic challenges in hormone-deficient states (66).

While testosterone replacement therapy (TRT) offers potential benefits for sexual function in hypogonadal men, its synergistic effects with PDE5i remain controversial (67). Complementary approaches, including lifestyle modifications and resistance training, are increasingly recognized as valuable anti-aging strategies that may ameliorate both hormonal and vascular components of ED (68). These interconnected pathways position ED as an early clinical manifestation of multisystem functional decline in aging males, emphasizing the need for comprehensive therapeutic strategies that address the complex interplay between endocrine, vascular, and metabolic factors in age-related ED (69).

Therapeutic strategies

Phosphodiesterase-5 inhibitors (PDE5i)

PDE5i remain foundational for treating ED by selectively inhibiting cGMP hydrolysis, thereby amplifying NO/cGMP signaling to enhance cavernosal smooth muscle relaxation (70). Clinically utilized agents—sildenafil, vardenafil, tadalafil, and avanafil—also demonstrate therapeutic value beyond ED, with sildenafil and tadalafil FDA-approved for pulmonary hypertension and showing cardioprotective potential in myocardial infarction and heart failure (71). Despite their efficacy, approximately 35% of patients, particularly those with severe vascular pathology like diabetic ED, exhibit poor responsiveness. First-generation inhibitors (sildenafil, vardenafil) further carry side effect risks due to off-target PDE6/PDE11 inhibition (72).

To overcome these limitations, combination strategies have emerged. Co-administration with antioxidants or daily low-dose tadalafil significantly improves outcomes without increasing adverse events, while synergy with testosterone in hypogonadal men elevates International Index of Erectile Function (IIEF) scores (73). Notably, it is hypothesized that pairing with angiotensin-converting enzyme inhibitors enhances efficacy, though α-blockers show minimal benefit (this conclusion is hypothesis-generating without human clinical data support). In observational studies, PDE5i are associated with a reduced risk of cardiovascular mortality following myocardial infarction (74).

Hormonal modulation

TRT constitutes a cornerstone intervention for age-related ED in hypogonadal men, primarily enhancing libido and improving mild ED symptoms by restoring physiological androgen levels (75). While effective in middle-aged and elderly populations, therapeutic responses exhibit significant interindividual variability, influenced by comorbidities that weaken the testosterone-ED correlation (76). TRT monotherapy often suffices for mild cases of androgen deficiency but demonstrates limited efficacy in severe ED, necessitating combination strategies (77). Controversy persists regarding synergistic effects with PDE5i, though clinical data suggest lifestyle modifications, particularly weight reduction, may yield comparable benefits to TRT, as decreased waist circumference independently correlates with erectile function improvement (78).

Beyond testosterone, age-related gonadal decline involves dysregulation of multiple hormones including follicle-stimulating hormone (FSH) and LH, collectively contributing to vascular and neuronal impairments underlying ED (79). Exogenous endocrine disruptors further complicate this landscape; estrogenic chemicals directly compromise erectile capacity via estrogen receptor α (Esr1)-mediated pathways, independent of hypogonadism (80). Collectively, hormonal management of age-associated ED requires personalized approaches. TRT addresses androgenic deficits but must be contextualized within broader metabolic health, with combination therapies and lifestyle interventions offering complementary value (81). Future research should clarify optimal TRT-PDE5i regimens while exploring endocrine disruptor mitigation strategies.

eNOS function preservation

Preserving eNOS function is critical for maintaining NO bioavailability in vascular aging and ED (82). Mitochondrial integrity plays a central role, as demonstrated by studies targeting cyclophilin D (CypD), a regulator of mitochondrial permeability transition pores (83). Endothelial-specific CypD knockout in murine models prevents angiotensin II-induced hypertension by preserving endothelial-dependent vasorelaxation and mitochondrial respiration while attenuating vascular oxidative stress and metabolic dysfunction (84). Smooth muscle-specific CypD depletion similarly reduces vascular superoxide and fibrosis, highlighting intercellular metabolic-redox crosstalk. These findings position CypD inhibition as a strategy to sustain eNOS-derived NO production and vascular homeostasis (85). Pharmacological, the flavonoid isorhamnetin activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/eNOS pathway in a diabetic model and enhances erectile function by reducing fibrosis of the corpus cavernosum and improving endothelial function → NO production → smooth muscle relaxation axis, while increasing the synthesis of endothelial marker (CD31) and NO (86). Conversely, elevated pigment epithelium-derived factor (PEDF) in diabetes impairs eNOS function by binding to extracellular Hsp90β (residues 341–724), disrupting intracellular Hsp90β/Akt/eNOS complex formation and phosphorylation (87). Neutralizing PEDF antibodies restore eNOS activity and erectile response in diabetic rodents, identifying PEDF as a therapeutic target (88). Compensatory mechanisms also emerge under NO deficiency: hydrogen sulfide (H₂S) synthesis via cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) increases in penile tissue during eNOS inhibition, providing alternative vasorelaxation and suggesting H₂S-based therapies for severe endothelial dysfunction (89). Finally, androgen deficiency exacerbates oxidative stress-mediated eNOS impairment, though antioxidants like resveratrol may indirectly support eNOS by upregulating endogenous antioxidant genes (90). Collectively, these approaches, targeting mitochondrial regulators, enhancing eNOS phosphorylation, blocking pathological inhibitors, leveraging compensatory gasotransmitters, and mitigating oxidative stress, converge on preserving eNOS functionality to combat vascular aging in ED (91).

Stem cell-based regeneration

Stem cell therapy represents a transformative approach for ED refractory to conventional treatments, leveraging multiple cell types, including adipose-derived stem cells (ADSCs), bone marrow mesenchymal stem cells (BM-MSCs), human umbilical cord MSCs (HUCMSCs), and human amniotic fluid stem cells (hAFSCs), to address distinct pathophysiological mechanisms (92). These cells primarily restore erectile function through direct tissue regeneration of cavernosal smooth muscle and endothelial cells, inhibition of diabetes-induced ferroptosis via NRP1/SLC7A11 interactions, and paracrine secretion of growth factors that enhance neurovascular repair (93). For diabetes mellitus ED (DMED), HUCMSCs reverse ferroptosis-mediated damage and restore erectile capacity in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) models, while BM-MSCs promote angiogenesis through VEGF-driven endothelial differentiation. In neurogenic ED, ADSCs transdifferentiate into neural-like cells or Schwann cells to regenerate injured cavernous nerves, whereas hAFSC-derived secretomes demonstrate efficacy in nerve crush models (94). For age-related ED, miR-145-engineered BM-MSCs mitigate vascular aging by targeting senescence pathways (95).

Technical innovations aim to overcome critical translational barriers: injectable hydrogels [e.g., polyethylene glycol (PEG)/chitosan] and biodegradable black phosphorus nanosheets (BPNS) significantly improve stem cell retention in the corpus cavernosum and enable targeted delivery of homing factors like SDF1-α to recruit endogenous progenitor cells via the CXCR4 axis (96). Exosome-based acellular therapies, particularly MSC-derived extracellular vesicles carrying miR-296-5p/miR-337-3p, replicate the regenerative effects of parent cells by suppressing phosphatase and tensin homolog (PTEN)/PI3K/AKT-mediated apoptosis and enhancing neuronal NO synthase, offering reduced risks compared to whole-cell transplantation (97). Genetic modifications further optimize efficacy, such as myocardin- or telomerase (hTERT)-overexpressing ADSCs that enhance tissue integration and oxidative stress resistance (98).

Despite promising preclinical outcomes, clinical adoption faces challenges including rapid cell dispersion in sinusoidal spaces, poor long-term survival, and potential complications like pulmonary microembolism. Early-phase human trials remain limited, necessitating strategies to improve biosafety and scalability. Future directions focus on combinatorial approaches, alternative cell sources like induced pluripotent stem cell-derived MSCs, and refined exosome engineering to harness endogenous repair mechanisms without cell transplantation risks (99). Collectively, stem cell-based paradigms hold significant potential for complex ED etiologies but require rigorous validation to bridge preclinical success to clinical practice.

Nanotechnology-enabled delivery

Nanotechnology offers transformative solutions for age-related ED by overcoming fundamental limitations of conventional therapies through precision targeting and enhanced bioavailability (100). Central to this approach are mesenchymal stem cell-derived exosomes (MSC-Exos), natural nanoparticles (30–200 nm) that serve as biological couriers for therapeutic cargo. When engineered to overexpress microRNA-145, these exosomes significantly restore erectile function in aged rats by regulating the PTEN/PI3K/AKT pathway and enhancing endothelial/smooth muscle homeostasis (101). Beyond natural vesicles, synthetic nanoplatforms enable advanced tissue-specific delivery: BPNS functionalized with SDF1-α recruit endogenous stem cells to repair cavernous nerve injuries (102), while polydopamine nanoparticle (PDNP)-modified exosomes encapsulated in thermosensitive hydrogels address the challenge of rapid dispersion in highly vascularized sinusoidal spaces through image-guided intratunical injection (103). For metabolic pathologies like diabetic ED, mitochondrion-targeting piezoelectric nanoparticles correct bioenergetic deficits by modulating autophagy and reducing oxidative stress in cavernosal pericytes, key cells identified in single-cell transcriptome studies as drivers of vascular dysfunction (104). Crucially, nanotechnology facilitates multi-target interventions, in preclinical studies using animal models, BPNS-based systems can simultaneously upregulate the expression of alpha-smooth muscle actin (α-SMA), CD31, and nNOS while reducing collagen deposition. In models of advanced vascular damage where conventional therapies are ineffective, these systems outperform PDE5 inhibitions (105). These platforms demonstrate superior efficacy and reduced off-target effects compared to systemic drugs, though optimization of degradation kinetics and long-term biocompatibility remains essential for clinical translation (106).

In general, the management of ED incorporates a spectrum of established therapeutic modalities, each exerting distinct impacts on reversing its pathophysiological mechanisms (Table 2). Intracavernosal injection/intraurethral administration (ICI/IU) improves erectile function via direct dilation of cavernosal blood vessels, which can correct vascular smooth muscle relaxation dysfunction but is ineffective in repairing endothelial injury or reversing arterial stiffness. Consistent, long-term utilization of vacuum erectile devices (VEDs) enhances local microcirculation and smooth muscle activity; however, their efficacy in addressing core pathological perturbations—such as reduced NO bioavailability—remains modest. Penile prosthesis implantation directly restores erectile function in patients with severe ED, yet it constitutes a symptomatic intervention that does not target the reversal of underlying pathological mechanisms and is associated with inherent surgical risks. In contrast, lifestyle interventions—including smoking cessation, alcohol moderation, a balanced diet, and regular physical activity—exert disease-modifying effects by directly targeting core etiologies like vascular aging and hormonal dysregulation. These interventions mitigate oxidative stress, attenuate inflammation, and improve endothelial function; long-term adherence can thus delay or even ameliorate the pathological progression of mild to moderate ED (107).

Conclusions

Conclusion and future perspectives

Based on the comprehensive review, age-related ED primarily stems from vascular aging, characterized by endothelial dysfunction, reduced NO bioavailability, vascular smooth muscle depletion, and arterial stiffness, exacerbated by chronic inflammation, oxidative stress, and hormonal imbalances. These interrelated mechanisms disrupt penile hemodynamics and neurovascular signaling, positioning ED as an early indicator of systemic vascular pathology. Current therapies like PDE5i and testosterone replacement offer symptomatic relief but exhibit limited efficacy in advanced vascular damage or metabolic comorbidities. Notably, among potential future strategies, targeting endothelial repair and NO bioavailability restoration (e.g., combining PDE5i with antioxidants or hormonal modulators) and stem cell-based cavernosal structure regeneration show considerable promise, as they directly address the core pathophysiological mechanisms of age-related ED. Additionally, nanotechnology-enabled precision delivery could further enhance the bioavailability of these therapeutic interventions to improve outcomes. Exploring biomarkers for early detection and developing personalized approaches focusing on mitochondrial integrity, inflammation resolution, and endothelial repair pathways also hold value for clinical translation. It is important to emphasize that the evidence supporting the aforementioned research models remains primarily at the preclinical stage. Thus, rigorous randomized controlled trials, long-term safety assessments, and comparative effectiveness studies are urgently needed to validate their clinical efficacy and safety before widespread clinical application.

Acknowledgments

We sincerely acknowledge the support from the Sanming Project of Medicine in Shenzhen (No. SZSM202103006).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-581/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-581/prf

Funding: This study was supported by Sanming Project of Medicine in Shenzhen (No. SZSM202103006).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-581/coif). The authors have no conflicts of interest to declare.

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