Faculty Collaboration Database

NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels. Basic Res Cardiol 2022 Apr 25;117(1):24

Date

04/27/2022

Pubmed ID

35469044

Pubmed Central ID

PMC9119129

DOI

10.1007/s00395-022-00932-9

Scopus ID

2-s2.0-85128849246 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

Impaired endothelium-dependent vasodilation has been suggested to be a key component of coronary microvascular dysfunction (CMD). A better understanding of endothelial pathways involved in vasodilation in human arterioles may provide new insight into the mechanisms of CMD. The goal of this study is to investigate the role of TRPV4, NOX4, and their interaction in human arterioles and examine the underlying mechanisms. Arterioles were freshly isolated from adipose and heart tissues obtained from 71 patients without coronary artery disease, and vascular reactivity was studied by videomicroscopy. In human adipose arterioles (HAA), ACh-induced dilation was significantly reduced by TRPV4 inhibitor HC067047 and by NOX 1/4 inhibitor GKT137831, but GKT137831 did not further affect the dilation in the presence of TRPV4 inhibitors. GKT137831 also inhibited TRPV4 agonist GSK1016790A-induced dilation in HAA and human coronary arterioles (HCA). NOX4 transcripts and proteins were detected in endothelial cells of HAA and HCA. Using fura-2 imaging, GKT137831 significantly reduced GSK1016790A-induced Ca²⁺ influx in the primary culture of endothelial cells and TRPV4-WT-overexpressing human coronary artery endothelial cells (HCAEC). However, GKT137831 did not affect TRPV4-mediated Ca²⁺ influx in non-phosphorylatable TRPV4-S823A/S824A-overexpressing HCAEC. In addition, treatment of HCAEC with GKT137831 decreased the phosphorylation level of Ser824 in TRPV4. Finally, proximity ligation assay (PLA) revealed co-localization of NOX4 and TRPV4 proteins. In conclusion, both TRPV4 and NOX4 contribute to ACh-induced dilation in human arterioles from patients without coronary artery disease. NOX4 increases TRPV4 phosphorylation in endothelial cells, which in turn enhances TRPV4-mediated Ca²⁺ entry and subsequent endothelium-dependent dilation in human arterioles.

Author List

Xie Y, Nishijima Y, Zinkevich NS, Korishettar A, Fang J, Mathison AJ, Zimmermann MT, Wilcox DA, Gutterman DD, Shen Y, Zhang DX

Authors

Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
David A. Wilcox PhD Professor in the Pediatrics department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
Natalya S. Zinkevich PhD Research Scientist I in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Arterioles
Coronary Artery Disease
Endothelial Cells
Endothelium, Vascular
Humans
NADPH Oxidase 4
Phosphorylation
TRPV Cation Channels
Vasodilation