Impaired Endothelium-Dependent Relaxation and Dysfunctional Piezo1 Channels in the Pudendal Artery and Corpus Cavernosum of Schlager Hypertensive (BPH/2J) Mice

Introduction/Objectives: Sexual dysfunction frequently affects individuals with hypertension and has a significant impact on the quality of life for men, women, and their partners. Hypertension affects vascular health, and thus it can induce structural and functional alterations in the vasculature supplying the penis, vagina, and clitoris. The vascular endothelium plays a crucial role in maintaining vascular tone and regulating blood pressure. Among the mechanosensors found in endothelial cells, Piezo1 emerges as a key player, being expressed in both endothelial and vascular smooth muscle cells. Moreover, Piezo1 deficiency contributes to the development of hypertension. However, it remains unclear whether Piezo1 channel activation is disrupted in the pudendal artery (PA) and corpus cavernosum (CC) in hypertension-induced sexual dysfunction. This study tested the hypothesis that Piezo1 channel function in the PA and CC of hypertensive mice is impaired, resulting in reduced dilation. Methods: For this, 14–15-month-old male and female hypertensive Schlager (BPH/2J) mouse, a polygenic model of hypertension, and their normotensive control strain BPN/3J mice were used. PA and CC were isolated and mounted in myographs for isometric force measurements. High extracellular KCl solution-induced contraction (80 mM) and concentration-response curves to phenylephrine (PE; 1 nM - 30 µM), acetylcholine (ACh; 1 nM - 30 µM), and Yoda2 (10 nM – 10 µM) were obtained. The contraction of CC induced by electrical field stimulation (EFS) was also evaluated. Data presented as mean ± S.E.M (n=3-4). The area under the curve (AUC) and non-linear regression curve were performed. Data were analyzed using Student's t -test (* p <0.05). Results: In PA from BPH/2J mice, KCl-induced contraction was significantly reduced in male (BPH/2J: 7.08±1.13* vs. BPN/3J: 11.92±0.96 mN) and female (BPH/2J: 3.39±0.99* vs. BPN/3J: 9.27±2.28 mN) mice. Similarly, PE-induced contraction was reduced in PA from male (E max BPH/2J: 10.35±1.09* vs. E max BPN/3J: 16.09±1.72 mN) and female (E max BPH/2J: 5.36±1.07* vs. E max BPN/3J: 12.42±1.83 mN) BPH/2J mice, whereas in CC, PE- and EFS-induced contractions were similar in both strains. On the other hand, ACh-induced relaxation was decreased in PA (E max BPH/2J: 65.60±6.65* vs. E max BPN/3J: 90.46±7.03%) and CC (AUC BPH/2J: 384.41±9.61* vs. AUC BPN/3J: 304.40±20.28) from male BPH/2J mice. Yoda2, a novel water-soluble Piezo1 channel activator, induced concentration-dependent relaxation in the PA from both male (AUC BPH/2J: 245.46±3.32* vs. AUC BPN/3J: 217.86±4.61) and female (AUC BPH/2J: 275.05±6.97* vs. AUC BPN/3J: 242.57±8.93) mice, however, it was impaired in BPH/2J mice. Similarly, Yoda2-induced relaxation was reduced in CC (AUC BPH/2J: 195.39±2.98* vs. AUC BPN/3J: 162.75±11.44) from BPH/2J mice. Conclusions: This study presents the first evidence of abnormalities in the PA and CC of BPH/2J mice. It also highlights that Piezo1 channel function is impaired in the CC and PA of both male and female hypertensive mice. NIH/NIDDK (R01DK132948 to RCW) and NIH/NHLBI (R01HL149762 to CFW) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.