Derangements in endothelial cell-to-cell junctions involved in the pathogenesis of hypercholesterolemia-induced erectile dysfunction.
BACKGROUND
Endothelial cell-to-cell junctions are crucial for vascular formation, networking, and remodeling of blood vessels as well as for inducing and integrating intracellular signals.


OBJECTIVE
We investigated the differential expression and distribution of endothelial cell-to-cell junction proteins in the penis of mice with hypercholesterolemia-induced erectile dysfunction.


METHODS
Two-month-old C57BL/6J mice were fed a diet containing 4% cholesterol and 1% cholic acid, and age-matched control animals were fed a normal diet, for 3 months. We performed dual priming oligonucleotide (DPO)-based multiplex polymerase chain reaction (PCR) (Seegene, Seoul, Korea) to screen the differential gene expression of 21 endothelial cell-to-cell junctions.


METHODS
At 5 months, erectile function was measured by electrical stimulation of the cavernous nerve, and the penis was harvested and stained with antibody to claudin-5, vascular endothelial (VE)-cadherin, and platelet/endothelial cell adhesion molecule (PECAM)-1 (N = 8 per group). Cavernous specimens from a separate group of animals were used for claudin-5, VE-cadherin, and PECAM-1 reverse transcriptase-PCR and Western blot analysis.


RESULTS
Erectile function was significantly lower in hypercholesterolemic mice than in controls. DPO-based multiplex PCR revealed a profound decrease in the gene expression of endothelium-specific cell-to-cell junction proteins, including claudin-5, VE-cadherin, and PECAM-1, in hypercholesterolemic mice compared with that in controls. The expression of claudin-5, VE-cadherin, and PECAM-1 protein evaluated by Western blot or immunohistochemistry was significantly lower in hypercholesterolemic mice than in controls. These endothelial cell-to-cell junction proteins were more sparsely distributed in the endothelium of cavernous sinusoids than in the endothelium of cavernous artery and dorsal blood vessels.


CONCLUSIONS
Down-regulation of the endothelial cell-to-cell junctions and decreased endothelial content in the corpus cavernosum might play a major role in the deterioration of erectile function in hypercholesterolemic mice.
Ryu
Ji-Kan
JK
Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, 7-206 3rd Street, Shinheung-Dong, Jung-Gu, Incheon, Korea.
Zhang
Lu Wei
LW
Jin
Hai-Rong
HR
Piao
Shuguang
S
Choi
Min Ji
MJ
Tuvshintur
Buyankhuu
B
Tumurbaatar
Munkhbayar
M
Shin
Sun Hwa
SH
Han
Jee-Young
JY
Kim
Woo Jean
WJ
Suh
Jun-Kyu
JK
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000150:complications*; D018783:Impotence, Vasculogenic / Q000209:etiology* / Q000235:genetics; D007365:Intercellular Junctions / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III; D010413:Penis / Q000187:drug effects / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D008565:Membrane Proteins; D052250:Nitric Oxide Synthase Type III; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5; C107466:CLDN5 protein, human; C496314:NOS3 protein, human