Zinc-sensing receptor activation induces endothelium-dependent hyperpolarization-mediated vasorelaxation of...

The micronutrient zinc (Zn²⁺) is critical for cell function as intracellular signaling and endogenous ligand for Zn²⁺ sensing receptor (ZnR). Although cytosolic Zn²⁺ (_cyt) signaling in the vascular system was studied previously, role of the ZnR has not been explored in vascular physiology.

ZnR-mediated relaxation response of human submucosal arterioles and the mesenteric arterioles from wide-type (WT), ZnR^-/- and TRPV4^-/- mice were determined by a Mulvany-style wire myograph. The perfused vessel density (PVD) of mouse mesenteric arterioles was also measured in in vivo study. The expression of ZnR in arterioles and vascular endothelial cells (VEC) were examined by immunofluorescence staining, and its function was characterized in VEC by Ca²⁺ imaging and patch clamp study.

ZnR expression was detected on human submucosal arterioles, murine mesenteric arterioles and VEC but not in ZnR^-/- mice. ZnR activation predominately induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of arterioles in vitro and in vivo via Ca²⁺ signaling, which is totally different from endothelium-dependent vasorelaxation via Zn²⁺ (_cyt) signaling reported previously. Furthermore, ZnR-induced vasorelaxation via EDH was significantly impaired in ZnR^-/- and TRPV4^-/- mice. Mechanistically, ZnR induced endothelium-dependent vasorelaxation predominately via PLC/IP₃/IP₃R and TRPV4/SOCE. The role of ZnR in regulating Ca²⁺ signaling and ion channels on VEC was verified by Ca²⁺ imaging and patch clamp techniques.

ZnR activation induces endothelium-dependent vasorelaxation of resistance vessels predominately via TRPV4/Ca²⁺/EDH pathway. We therefore not only provide new insights into physiological role of ZnR in vascular system but also may pave a potential pathway for developing Zn²⁺-based treatments for vascular disease.