The pericyte as a cellular regulator of penile erection and a novel therapeutic target for erectile dysfunction

Abstract

Pericytes are known to play critical roles in vascular development and homeostasis. However, the distribution of cavernous pericytes and their roles in penile erection is unclear. Herein we report that the pericytes are abundantly distributed in microvessels of the subtunical area and dorsal nerve bundle of mice, followed by dorsal vein and cavernous sinusoids. We further confirmed the presence of pericytes in human corpus cavernosum tissue and successfully isolated pericytes from mouse penis. Cavernous pericyte contents from diabetic mice and tube formation of cultured pericytes in high glucose condition were greatly reduced compared with those in normal conditions. Suppression of pericyte function with anti-PDGFR-β blocking antibody deteriorated erectile function and tube formation in vivo and in vitro diabetic condition. In contrast, enhanced pericyte function with HGF protein restored cavernous pericyte content in diabetic mice, and significantly decreased cavernous permeability in diabetic mice and in pericytes-endothelial cell co-culture system, which induced significant recovery of erectile function. Overall, these findings showed the presence and distribution of pericytes in the penis of normal or pathologic condition and documented their role in the regulation of cavernous permeability and penile erection, which ultimately explore novel therapeutics of erectile dysfunction targeting pericyte function.

Penile neurovascular structure revisited: immunohistochemical studies with three‐dimensional reconstruction

“…In this study, we established three‐dimensional images of penile vasculature using makers for endothelial cells, smooth muscle cells, and pericytes. Similar to the results from ours (Yin et al ., ), we observed the intense expression of NG2‐positive pericytes around microvessels at the subtunical area, followed by the dorsal nerve bundle, dorsal vein, and cavernous sinusoids. The majority of endothelial layer of the cavernous artery or dorsal artery was covered with smooth muscle cells and rarely associated with smooth muscle cells, whereas endothelial layer of the cavernous sinusoids or dorsal vein was intermingled with pericytes and smooth muscle cells.…”

“…With three‐dimensional imaging technique, we also documented obvious structural changes of key components of penile erection (Andersson, ; Yin et al ., ), such as endothelial cells, pericytes, smooth muscle cells, and nerve fibers, in diabetic condition. It allows a better understanding of the origin and the course of the nervous elements as well as distribution of vascular components involved in physiologic penile erection or in ED from pathologic conditions.…”

“…Penile erection is a neurovascular phenomenon that requires well coordinated and functional interaction between vascular endothelial cells, smooth muscle cells, pericytes, and neuronal cells (Andersson, ; Yin et al ., ). Nitric oxide (NO), mainly derived from nonadrenergic and noncholinergic nerves and from cavernous endothelium, diffuses into the adjacent cavernous smooth muscles and reacts with guanylylate cyclases, which catalyze the conversion of GTP to GMP.…”

“…We observed the loss of pericytes and a subsequent increase in the vascular permeability in corpus cavernosum of the diabetic mice. Moreover, inhibition of pericyte function with anti‐platelet‐derived growth factor receptor‐β has been shown to induce deterioration of erectile function in normal mice (Yin et al ., ).…”

“…Functional and structural impairments of endothelial cells, smooth muscle cells, pericytes, and neuronal cells play a critical role in the pathophysiology of erectile dysfunction (ED) (Andersson, ; Yin et al ., ). Diabetes mellitus is one of the main causes of ED and multiple pathogenic factors, such as cavernous angiopathy and autonomic neuropathy, are involved in diabetic ED (Lue, ).…”