Yes-Associated Protein Promotes Endothelial-Mesenchymal Transition to Mediate Diabetes Mellitus Erectile Dysfunction by Phosphorylating Smad3

Purpose: The main objective of this study is to elucidate the role of endothelial-mesenchymal transition (EndMT) regulated by yes-associated protein (YAP) on diabetes mellitus erectile dysfunction (DMED).

Materials and methods: High concentrations of glucose and palmitic acid (HGP) culturing simulated a diabetic condition in vitro. Cell proliferation, migration, tube formation, and marker gene changes of rat cavernous endothelial cells (RCECs) were measured after YAP overexpression or knockdown. Erectile function and histological outcomes were evaluated in vivo.

Results: Nuclear YAP in RCECs was significantly increased after pretreatment with HGP. YAP overexpression enhanced the cell proliferation (0.236±0.004 vs. 0.148±0.008, p<0.001), migration (1.908±0.099 vs. 1.000±0.116, p<0.001), and tube formation (290.6±10.96 and 21,440.3±762.9 vs. 175.0±24.82 and 13,538.6±1,819.0, p<0.001) compared to the control group. Moreover, the ratios of intracavernous pressure (ICP) to mean arterial pressure (MAP) (0.642±0.051 vs. 0.850±0.070, p<0.05), and smooth muscle to collagen (0.155±0.010 vs. 0.274±0.023, p<0.01) were decreased in rats with YAP overexpression. The effects of HGP on CD31, eNOS, CD34, VE-cadherin, vimentin, α-SMA, and p-Smad3 expression were abrogated by inhibiting YAP in RCECs. YAP knockdown also restored the ICP/MAP (0.597±0.019 vs. 0.346±0.033, p<0.01), smooth muscle/collagen (0.13±0.010 vs. 0.08±0.026, p<0.05) and p-Smad3/Smad3 (1.61±0.291 vs. 3.26±0.332, p<0.01) ratios in type 2 diabetic rats.

Conclusions: YAP promotes EndMT to impair erectile function in type 2 diabetic rats by phosphorylating Smad3, providing a new strategy for treating DMED.