Alteration of Piezo1 signaling in type 2 diabetic mice: focus on endothelium and BKCa channel.

Piezo1 mechanosensitive ion channel plays a important role in vascular physiology and disease. This study aimed to elucidate the altered signaling elicited by Piezo1 activation in the arteries of type 2 diabetes. Ten- to 12-week-old male C57BL/6 (control) and type 2 diabetic mice (db^-/db^-) were used. The second-order mesenteric arteries (~ 150 μm) were used for isometric tension experiments. Western blot analysis and immunofluorescence staining were performed to observe protein expression. Piezo1 was significantly decreased in mesenteric arteries of type 2 diabetic mice compared to control mice, as analyzed by western blot and immunofluorescence staining. Piezo1 agonist, Yoda1, concentration-dependently induced relaxation of mesenteric arteries in both groups. Interestingly, the relaxation response was significantly greater in control mice than in db^-/db^- mice. The removal of endothelium reduced relaxation responses induced by Yoda1, which was greater in control mice than db^-/db^- mice. Furthermore, the relaxation response was reduced by pre-treatment with various types of K⁺ channel blockers in endothelium-intact arteries in control mice. In endothelium-denuded arteries, pre-incubation with charybdotoxin, an Ca²⁺-activated K⁺ channel (BK_Ca channel) blocker, significantly attenuated Yoda1-induced relaxation in db^-/db^- mice, while there was no effect in control mice. Co-immunofluorescence staining showed co-localization of Piezo1 and BK_Ca channel was more pronounced in db^-/db^- mice than in control mice. These results indicate that the vascular responses induced by Piezo1 activation are different in the mesenteric resistance arteries in type 2 diabetic mice.