ED 11. Incompetent cavernous endothelial cell - cell junction is responsible for why erectile dysfunction is highly prevalent and precedes other systemic vascular diseases: endothelial cell - cell junction hypothesis

Objective: Erectile dysfunction (ED) is highly prevalent in adult male and is often regarded as a silent marker for serious systemic vascular diseases. Exact mechanism by which ED occurs prior to systemic vascular diseases remains to be elucidated, although artery size hypothesis has been suggested. We, herein, performed a comprehensive study to answer this question.

Design and Methods: Methods: Either hypercholesterolemia or diabetes was induced by feeding a high-cholesterol diet for 3 months or by intraperitoneal injection of streptozotocin (50 mg/kg for 5 days), respectively, in 8-week-old C57BL/6J mice. Erectile function was measured by electrical stimulation of the cavernous nerve, and the penis was harvested and stained for endothelial cell-cell (EC-EC) junction proteins. Penis specimens from a separate group of animals were used for western blot analysis of EC-EC junction proteins. We determined vascular endothelial permeability in the penis, heart, hindlimb, brain, and testis after injection of a variety of vascular space markers (350 Da to 2000 kDa) into the jugular vein. We also investigated the effect of recombinant angiopoietin-1 (Ang1), an anti-permeability factor, on the cavernous endothelial permeability in diabetic mice.

Results: The cavernous expression of EC-EC junctions in mice, including VE-cadherin, claudin-5, and PECAM-1, was significantly lower in hypercholesterolemic or diabetic groups than in controls. These EC-EC junction proteins were more sparsely distributed in endothelium of cavernous sinusoids than in endothelium of cavernous artery and dorsal blood vessels. We observed a significant leakage of fluorescent tracer across the cavernous endothelium, whereas minimal leakage in heart and hindlimb or no leakage in brain and testis was noted in normal mice. Moreover, endothelium of cavernous sinusoids was much more permeable to vascular tracers in hypercholesterolemic and diabetic condition than in normal condition. Intracavernous injection of Ang1 protein decreased cavernous endothelial permeability by restoring EC-EC junction proteins and induced recovery of erectile function and in diabetic mice.

Conclusions: Incompetent cavernous endothelial cell-cell junction gives us an important clue to understanding why ED is highly prevalent and often precedes the occurrence of other systemic vascular diseases.