Regulatory role of Piezo1 channel in endothelium-dependent hyperpolarization-mediated vasorelaxation of small resistance vessels and its anti-inflammatory action

Although endothelial Piezo1 channel is known to induce NO-mediated vasorelaxation of conduit vessels, it remains largely unknown if it can induce endothelial-dependent hyperpolarization (EDH)-mediated vasorelaxation of resistance vessels. Therefore, the present study aims to investigate Piezo1/EDH-mediated vasorelaxation in health and its involvement in ulcerative colitis (UC) and sepsis, two intractable and deadly inflammatory diseases.The tension of the second-order branch of mouse mesenteric artery was measured via the Danish DMT600M microvascular measurement system. The changes in cytoplasmic calcium ([Ca2+]cyt) signaling in vascular endothelial cells were detected by fluorescent calcium assay, and the membrane potential changes were monitored by patch clamp. Experimental murine models of UC and sepsis were induced by dextran sulfate sodium (DSS) and lipopolysaccharides (LPS), respectively.A selective activator of Piezo1 channel, Yoda1, dose-dependently induced vasorelaxation of the second-order branch of mouse mesenteric artery in an endothelium-dependent manner. The endothelial Piezo1 channel mediated the vasorelaxation through EDH mechanism by a functional coupling of Piezo1 and TRPV4 channels. Their function and coupling were verified by [Ca2+]cyt imaging and patch clamp study in single endothelial cells. Moreover, while ACh-induced vasorelaxation played a major role in health, it was significantly impaired in the pathogenesis of UC and sepsis; however, Piezo1/EDH-mediated vasorelaxation remained intact. Finally, Piezo1/EDH-mediated vasorelaxation recovered ACh-induced vasorelaxation impaired in UC and sepsis.Piezo1/TRPV4/EDH-mediated vasorelaxation rescues the impaired ACh-induced vasorelaxation to likely recover hemoperfusion to organs, leading to organ protection against UC and sepsis. Our study not only suggests that endothelial Piezo1, TRPV4 and KCa channels are the potential therapeutic targets, but also implies that Piezo1 activators may benefit to prevent/treat UC and sepsis.