Internal Pudendal Artery from Type 2 Diabetic Female Rats Demonstrate Elevated Endothelin-1-Mediated Constriction

Abstract

Introduction Diabetes is a risk factor for female sexual dysfunction (FSD). FSD has several etiologies, including a vasculogenic component that could be exacerbated in diabetes. The internal pudendal artery supplies blood to the vagina and clitoris and diabetes-associated functional abnormalities in this vascular bed may contribute to FSD. Aim The Goto-Kakizaki (GK) rat is a non-obese model of type 2 diabetes with elevated endothelin-1 (ET-1) activity. We hypothesize that female GK rats have diminished sexual responses and that the internal pudendal arteries demonstrate increased ET-1 constrictor sensitivity. Methods Female Wistar and GK rats were used. Apomorphine (APO)-mediated genital vasocongestive arousal (GVA) was measured. Functional contraction (ET-1 and phenylephrine) and relaxation (acetylcholine, ACh) in the presence or absence of the ETA receptor antagonist (ETAR; atrasentan) or Rho-kinase inhibitor (Y-27632) were assessed in the internal pudendal and mesenteric arteries. Protein expression of ET-1 and RhoA/Rho-kinase signaling pathway was determined in the internal pudendal and mesenteric arteries. Main Outcome Measure APO-mediated GVAs; contraction and relaxation of internal pudendal and mesenteric arteries; ET-1/RhoA/Rho-kinase protein expression. Results GK rats demonstrated no APO-induced GVAs. Internal pudendal arteries, but not mesenteric arteries, from GK rats exhibited greater contractile sensitivity to ET-1 compared with Wistar arteries. ETAR blockade reduced ET-1-mediated constriction in GK internal pudendal and mesenteric arteries. Rho-kinase inhibition reduced ET-1-mediated constriction of GK internal pudendal but not mesenteric arteries; however, it had no effect on arteries from Wistar rats. RhoA protein expression was elevated in GK internal pudendal arteries. At the highest concentrations, ACh-mediated relaxation was greater in the GK internal pudendal artery; however, no difference was observed in the mesenteric artery. Conclusions Female GK rats demonstrate decreased sexual responses that may be because of increased constrictor sensitivity to the ET-1/RhoA/Rho-kinase signaling in the internal pudendal artery.

Characterization of the Vasculature Supplying the Genital Tissues in Female Rats

“…Additionally, these atherosclerotic animals displayed diminished vaginal and clitoral blood flow and pressure [37]. Type I and II diabetic rats and mice have shown degenerative changes in vaginal and clitoral integrity leading to impaired genital blood flow [19,38–40]. The type II diabetic Goto‐Kakizaki rat has increased internal pudendal artery sensitivity to endothelin‐1 via the RhoA/Rho‐kinase pathway and is unable to achieve genital vasocongestive arousal [19].…”

“…The pudendal artery's response to endothelin‐1 and its signaling pathway was recently characterized [18]. Additionally, pudendal arteries from female type 2 diabetic rats exhibiting diminished vasocongestive arousal responses had increased constrictor sensitivity to endothelin‐1 via the downstream RhoA/Rho‐kinase signaling pathway [19]. The current study sought to characterize the internal pudendal artery anatomically and morphologically in the female rat.…”

Internal Pudental Artery Dysfunction in Diabetes Mellitus Is Mediated by NOX1-Derived ROS-, Nrf2-, and Rho Kinase–Dependent Mechanisms

“…Regarding a role for Nrf2/Rho kinase in the erectile function process, it has been reported that increased Rho kinase activity contributes to impaired corpora cavernosa relaxation in streptozotocin-induced DM 55 and also in db/db mice, an experimental model that exhibit downregulation of Nrf2-regulated antioxidant enzymes. 56 Rho kinase inhibition also reduces ET-1-mediated IPA constriction in type 2 diabetic female rats 12 and increases intracavernosal pressure and rat penile erection induced by cavernous nerve stimulation. 57 Our data showing that Rho kinase activation in IPA from diabetic mice is an event regulated by NOX1-derived ROS further highlight the relevance of IPA-Nrf2/Rho kinase in the erectile function process and indicate that NOX1 inhibitors and Nrf2 activators may be important candidates to treat ED associated with Rho kinase-induced IPA dysfunction.…”

“…10 Although it may be expected that IPA display DM-associated dysfunction, 11 almost no studies have addressed the function of IPA in DM. 12 Hyperglycemia, hyperlipidemia, and inflammation, 3 main metabolic abnormalities in DM, induce reactive oxygen species (ROS) generation and oxidative stress. Oxidative stress, defined as a disturbance in the production of ROS or in the ability of the antioxidant defenses to neutralize ROS, is critically involved in DM-associated complications, including nephropathy, cardiomyopathy, endothelial dysfunction, and ED.…”

Therapeutic implications of peptide interactions with G‐protein‐coupled receptors in diabetic vasculopathy

“…, Allahdadi et al . ) and endothelial ET B ‐receptor‐mediated vasodilatation is reduced (Makino & Kamata , Llorens et al . , Matsumoto et al .…”