(001) IMPAIRED PIEZO1 FUNCTION IN THE PUDENDAL ARTERY AND CORPUS CAVERNOSUM OF HYPERTENSIVE MICE LEADING TO REDUCED DILATION

Abstract Introduction Hypertension is a common clinical condition that has been associated with a negative impact on sexual function in both men and women. Hypertension affects vascular health, and thus it can induce structural and functional alterations in the vasculature supplying the penis, vagina, and clitoris. Piezo1 is a mechanosensitive channel that senses shear stress and cell stretch. It is expressed in endothelial and vascular smooth muscle cells, regulating vascular tone and blood pressure. The activation of the Piezo1 channel leads to an increase in intracellular calcium, which activates endothelial nitric oxide (NO) synthase, resulting in the production of NO and promoting dilation. Moreover, Piezo1 deficiency is associated with the development of hypertension. Our group has previously demonstrated that Piezo1 is expressed in pudendal artery (PA) and corpus cavernosum (CC) of rats. However, whether Piezo1 channel activation is disrupted in PA and CC in hypertension remains unclear. Objective We aimed to test the hypothesis that Piezo1 channel function in PA and CC of hypertensive mice is impaired leading to reduced dilation. Methods For this, 14–15-month-old male and female hypertensive Schlager (BPH/2 J) mouse, a polygenic model of hypertension, and their normotensive control strain BPN/3 J mice were used. PA and CC were isolated and mounted in myograph for isometric force measurements. KCl-induced contraction (80 mM) and concentration-response curves to phenylephrine (PE; 1 nM - 30 uM), acetylcholine (ACh; 1 nM - 30 uM), and Yoda2 (10 nM–100 uM) were obtained. Moreover, the contraction of CC induced by electrical field stimulation (EFS) was evaluated. Data are mean +/- S.E.M of 3-4 mice. Additionally, the area under the curve and non-linear regression curve were performed. The data were analyzed using Student t-test (*p-value is less than 0.05). Results BPH/2 J mice presented reduced KCl contraction in PA from male (BPH/2 J: 7.08+/-1.13* vs. BPN/3 J: 11.92+/-0.96 mN) and female (BPH/2 J: 3.39+/-0.99* vs. BPN/3 J: 9.27+/-2.28 mN) mice. Similarly, PE-induced contraction was reduced in PA from male (Emax BPH/2 J: 10.35+/-1.09* vs. Emax BPN/3 J: 16.09+/-1.72 mN) and female (Emax BPH/2 J: 5.36+/-1.07* vs. Emax BPN/3 J: 12.42+/-1.83 mN) BPH/2 J mice. On the other hand, PE-induced contraction was similar in CC (Emax BPH/2 J: 1.65+/-0.28 vs. Emax BPN/3 J: 1.68+/-0.32 mN) from BPN/3 J and BPH/2 J mice. Moreover, the EFS-induced contraction was similar between CC from BPN/3 J and BPH/2 J mice. ACh-dependent relaxation was decreased in PA from male BPH/2 J mice (Emax BPH/2 J: 65.60+/-6.65* vs. Emax BPN/3 J: 90.46+/-7.03%). Yoda2, a novel potent and water-soluble Piezo1 channel agonist, induced concentration-dependent relaxation in the PA from both male and female mice, however, it was impaired in BPH/2 J mice. Similarly, Yoda2-induced relaxation was reduced in CC from BPH/2 J mice. Conclusions This study revealed, for the first time, PA and CC dysfunction in hypertensive BPH/2 J mice. Moreover, Piezo1 function is impaired in the PA from both male and female hypertensive mice. Disclosure No.