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

作者全名："Zhang, Luyun; Sunchen, Sijin; Lu, Cheng; Xu, Feng; Dong, Hui"

作者地址："[Zhang, Luyun; Xu, Feng; Dong, Hui] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Dept Rehabil,Childrens Hosp,Dept Pediat Intens Car, Chongqing, Peoples R China; [Zhang, Luyun; Sunchen, Sijin; Dong, Hui] Qingdao Univ, Sch Pharm, Dept Pharmacol, Med Coll, 1 Ningde Rd, Qingdao 266073, Peoples R China; [Lu, Cheng] Army Med Univ, Xinqiao Hosp, Dept Gastroenterol, Chongqing 400037, Peoples R China"

通信作者："Xu, F; Dong, H (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Dept Rehabil,Childrens Hosp,Dept Pediat Intens Car, Chongqing, Peoples R China.; Dong, H (通讯作者)，Qingdao Univ, Sch Pharm, Dept Pharmacol, Med Coll, 1 Ningde Rd, Qingdao 266073, Peoples R China."

来源：BIOCHEMICAL PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001137414100001

JCR分区：Q1

影响因子：5.8

年份：2024

卷号：219

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Zn 2+sensing receptor; Endothelium-derived hyperpolarization; TRPV4; SOCE

摘要："Background: 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. Methods: 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. Results: 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. Conclusion: 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."

基金机构：National Nat-ural Science Foundation of China [82273115]

基金资助正文：<BOLD>Funding</BOLD> This work was supported by research grants from the National Nat-ural Science Foundation of China (No.82273115 to HD) .