Abstract Body: Introduction: The association between hypertension and sexual dysfunction is well established, but the underlying mechanisms and sex-specific manifestations are not yet fully understood, particularly regarding its impact on female sexual function. Vasculogenic erectile dysfunction (ED) is often the very first sign of a change in cardiovascular health and precedes the onset of a significant cardiovascular event, such as a heart attack, by 3 to 5 years. Although the hypertensive Schlager (BPH/2J) mouse is increasingly used as a polygenic model of neurogenic hypertension, sexual dysfunction in this strain has not been investigated. Since ED can be an early manifestation of vascular disease and hypertension-related vascular changes often involve dysregulation of mechanosensitive ion channels like Piezo1, it remains unknown whether Piezo1 channels are altered in the pudendal artery (PA) and corpus cavernosum (CC) of BPH/2J mice. This study tested the hypothesis that impaired Piezo1 channel function contributes to pudendal and cavernosal dysfunction in BPH/2J mice, leading to reduced dilation. Methods: Male and female BPH/2J mice (14–15 months) and normotensive controls (BPN/3J) were used. PA and CC were isolated for isometric force recordings. The smooth muscle-to-collagen ratio was assessed using Masson's trichrome staining. Data are expressed as mean ± S.E.M. (n=3–4). The area under the curve (AUC) and nonlinear regression analyses were performed. Statistical comparisons used Student’s t-test (*p<0.05). Results: KCl- and PE-induced contractions were reduced in the 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. In contrast, PE- and EFS-induced contractions in the CC were similar between strains. 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, Piezo1 activator, caused concentration-dependent relaxation in PA from both sexes and CC, but responses were significantly impaired in BPH/2J mice. The smooth muscle-to-collagen ratio (%) did not differ between mouse strains in either the male PA or the CC. Conclusions: These findings provide the first evidence of functional abnormalities in the PA and CC of hypertensive BPH/2J mice and demonstrate impaired Piezo1-mediated cavernosal and pudendal responses in both sexes.