Deficiency of endothelial TRPV4 cation channels ameliorates experimental abdominal aortic aneurysm

She-Hua Qian; Shuai Liu; Mi Wang; Qing Wang; Chang-Ping Hu; Jun-Hao Huang; Zheng Zhang

doi:10.1016/j.ejphar.2024.177150

Deficiency of endothelial TRPV4 cation channels ameliorates experimental abdominal aortic aneurysm

Eur J Pharmacol. 2024 Nov 20:986:177150. doi: 10.1016/j.ejphar.2024.177150. Online ahead of print.

Authors

She-Hua Qian¹, Shuai Liu², Mi Wang³, Qing Wang⁴, Chang-Ping Hu⁵, Jun-Hao Huang⁶, Zheng Zhang⁷

Affiliations

¹ Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.
² Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
³ Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
⁴ Department of the Interventional Radiology & Vascular Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, Hunan, China.
⁵ Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410013, Hunan, China.
⁶ Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion, Guangzhou Sport University, Guangzhou, 510050, Guangdong, China. Electronic address: junhaohuang2006@hotmail.com.
⁷ Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410013, Hunan, China. Electronic address: zzhang@csu.edu.cn.

PMID: 39577553
DOI: 10.1016/j.ejphar.2024.177150

Abstract

Background: Abdominal aortic aneurysm (AAA), albeit usually asymptomatic, is highly lethal if ruptured. The 28-member transient receptor potential (TRP) ion channel superfamily, most of which are present in the aortic cells, is understudied in AAA. We aim to identify single TRP channel that could represent a novel therapeutic target, and dissect dysfunctional ionic signaling that drives AAA.

Methods: AAA was developed in mice by perfusing porcine pancreatic elastase into the infrarenal abdominal aorta. AAA was assessed by measurement of external diameter with a digital caliper, or internal diameter with ultrasonography. Aortic pathohistology was evaluated via histological and immunohistochemical staining. The TRP channel family was analyzed in the GSE17901 dataset. TRPC6, TRPC1/4/5 and TRPC3 channels were blocked in aneurysmal mice by BI749327, Pico145 and Pyr3, respectively. Endothelial cell-selective Trpv4 knockout mice were generated and leveraged for AAA analysis. TRPV4 channel was activated indirectly by TPPU or directly opened by GSK1016790A.

Results: RNA-seq data mining revealed altered expression profiles of Trpc3/Trpc6, Trpv4. Pharmacological block of TRPC6, TRPC1/4/5 or TRPC3 did not influence AAA, whereas selective deletion of endothelial TRPV4 protected against AAA in endothelial cell-selective Trpv4 knockout mice. Indirect activation of TRPV4 by TPPU exacerbated AAA, but TRPV4-mediated nitric oxide signaling contributed minimally to AAA. TRPV4 activation promoted endothelial cell apoptosis in a Ca²⁺-dependent manner, a relevant mechanism underlying AAA.

Conclusions: Our data underscore the pathogenic importance of Ca²⁺ perturbation in AAA and illuminate that endothelial TRPV4 cation channel could be harnessed for AAA treatment.

Keywords: Abdominal aortic aneurysm; Apoptosis; Endothelial cells; Transient receptor potential vanilloid subtype 4.