Endothelial cell Orai1 is essential for endothelium-dependent contraction of mouse carotid arteries in normotensive and hypertensive mice  

作　　者：Xiao Li Zhen-chuan Lei Chun Yin Lo Tsz Yau Jan Chi Wai Lau Xiao-qiang Yao 

机构地区：[1]School of Biomedical Sciences,Heart and Vascular Institute and Li Ka Shing Institute of Health Science,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong,China [2]Centre for Cell&Developmental Biology,School of Life Sciences,The Chinese University of Hong Kong,Hong Kong,China

出　　处：《Acta Pharmacologica Sinica》2024年第5期975-987,共13页中国药理学报（英文版）

基　　金：supported by grants from Hong Kong Research Grant Committee(14100619,RIF/R4005-18F)and Innovation and Technology Fund ITS/212/21.

摘　　要：Endothelium-dependent contraction(EDC)exists in blood vessels of normotensive animals,but is exaggerated in hypertension.An early signal in EDC is cytosolic Ca2+rise in endothelial cells.In this study we investigated the functional role of Orai1,a major endothelial cell Ca2+entry channel,in EDC.Hypertension model was established in WT mice by intake of L-NNA in the drinking water(0.5 g/L)for 4 weeks or osmotic pump delivery of Ang II(1.5 mg·kg^(−1)·d^(−1))for 2 weeks.In TRPC5 KO mice,the concentration of L-NNA and Ang II were increased to 1 g/L or 2 mg·kg^(−1)·d^(−1),respectively.Arterial segments were prepared from carotid arteries and aortas,and EDC was elicited by acetylcholine in the presence of Nω-nitro-L-arginine methyl ester.We showed that low concentration of acetylcholine(3-30 nM)initiated relaxation in phenylephrine-precontracted carotid arteries of both normotensive and hypertensive mice,while high concentration of acetylcholine(0.1-2μM)induced contraction.Application of selective Orai1 inhibitors AnCoA4(100μM)or YM58483(400 nM)had no effect on ACh-induced relaxation but markedly reduced acetylcholine-induced EDC.We found that EDC was increased in hypertensive mice compared with that of normotensive mice,which was associated with increased Orai1 expression in endothelial cells of hypertensive mice.Compared to TRPC5 and TRPV4,which were also involved in EDC,endothelial cell Orai1 had relatively greater contribution to EDC than either TRPC5 or TRPV4 alone.We identified COX-2,followed by PGF2α,PGD2 and PGE2 as the downstream signals of Orai1/TRPC5/TRPV4.In conclusion,Orai1 coordinates together with TRPC5 and TRPV4 in endothelial cells to regulate EDC responses.This study demonstrates a novel function of Orai1 in EDC in both normotensive and hypertensive mice,thus providing a general scheme about the control of EDC by Ca2+-permeable channels.

关 键 词：carotid artery endothelium-dependent contraction ACETYLCHOLINE Orai1 hypertension 

分 类 号：R363[医药卫生—病理学]