ER Stress Induces Endothelial Dysfunction Linked to Mitochondrial Redox Imbalance and Enhanced Mitochondrial Bioenergetics in Penile Erectile Tissue

Endoplasmic reticulum (ER) stress has been proposed as a link between insulin resistance, oxidative stress, and endothelial dysfunction in metabolic disorders. Penile erectile dysfunction shares risk factors with cardiovascular disease (CVD) including insulin resistance, diabetes, and obesity. In the present study, involvement of ER stress in penile endothelial and vascular dysfunction was investigated in an in vivo model of ER stress induced by tunicamycin. Endothelial function was assessed by using wire myography, mitochondrial reactive oxygen species (mtROS) by mitoSOX and Amplex Red fluorometry, mitochondrial bioenergetics by Seahorse XF Analyzer, and expression of ER-stress markers by Western blot. Tunicamycin increased expression of BiP, pPERK, ATF6α, and pIRE1α in penile erectile tissue. Endothelium-dependent relaxations to acetylcholine were impaired, while α1-adrenergic vasoconstriction was blunted in penile arteries from ER-stress rats. Selective NADPH oxidase 1 (Nox1) inhibition restored endothelial relaxations, while blockade of Nox2 and Nox4 revealed H2O2-mediated endothelial relaxations in control but not in tunicamycin-treated rats. ER stress reduced basal mtROS levels and mitoTEMPO- sensitive relaxant responses. On the other hand, enhanced mitochondrial respiration and glycolytic activity were found in penile arteries from tunicamycin-treated rats. These findings indicate that ER stress blunts adrenergic vasoconstriction, and induces endothelial dysfunction by enhancing Nox1-derived ROS and reducing mitochondrial vasodilator H2O2. Attenuation of ER stress emerges as a potential therapeutic target in the management of metabolic disease-associated erectile dysfunction.