Activation of ATP‐sensitive potassium channels facilitates the function of human endothelial colony‐forming cells via Ca2+/Akt/eNOS pathway

Yan Wu,Hui Kong,Shu‐Ying Ma,Meng‐Yu He,Yong‐Yue Wei,Wei‐Ping Xie,Xiao‐Ning Zeng,Jian‐Kui Ye,Wen Huang,Hong Wang

doi:10.1111/jcmm.13006

Abstract

Accumulating data, including those from our laboratory, have shown that the opening of ATP‐sensitive potassium channels (KATP) plays a protective role in pulmonary vascular diseases (PVD). As maintainers of the endothelial framework, endothelial colony‐forming cells (ECFCs) are considered excellent candidates for vascular regeneration in cases of PVD. Although KATP openers (KCOs) have been demonstrated to have beneficial effects on endothelial cells, the impact of KATP on ECFC function remains unclear. Herein, this study investigated whether there is a distribution of KATP in ECFCs and what role KATP play in ECFC modulation. By human ECFCs isolated from adult peripheral blood, KATP were confirmed for the first time to express in ECFCs, comprised subunits of Kir (Kir6.1, Kir6.2) and SUR2b. KCOs such as the classical agent nicorandil (Nico) and the novel agent iptakalim (Ipt) notably improved the function of ECFCs, promoting cell proliferation, migration and angiogenesis, which were abolished by a non‐selective KATP blocker glibenclamide (Gli). To determine the underlying mechanisms, we investigated the impacts of KCOs on CaMKII, Akt and endothelial nitric oxide synthase pathways. Enhanced levels were detected by western blotting, which were abrogated by Gli. This suggested an involvement of Ca2+ signalling in the regulation of ECFCs by KATP. Our findings demonstrated for the first time that there is a distribution of KATP in ECFCs and KATP play a vital role in ECFC function. The present work highlighted a novel profile of KATP as a potential target for ECFC modulation, which may hold the key to the treatment of PVD.

Highlights

ATP-sensitive potassium channels (KATP), widely expressed in tissues and cells, participate in numerous cellular processes
We revealed that KATP openers (KCOs) could promote endothelial colony-forming cells (ECFCs) proliferation, migration and angiogenesis by Ca2+/Akt/endothelial nitric oxide synthase signalling, which will improve our understanding on the respiratory biology of KATP and open new perspectives for ECFC management
Based on surface markers and the culture methods used, circulating Endothelial progenitor cells (EPCs) have been divided into three groups: colony-forming unit endothelial cells (ECs) (CFU-ECs), circulating angiogenic cells (CACs) and ECFCs [10, 23]

Summary

Introduction

ATP-sensitive potassium channels (KATP), widely expressed in tissues and cells, participate in numerous cellular processes. Mounting evidence has confirmed that KATP protect myocardium against ischaemia, regulate vascular smooth muscle contraction and are involved in the secretion of insulin from pancreatic b cells [1]. Prevailing attention has been paid to the regulatory role of KATP in endothelial cells (ECs). As the major components of the pulmonary vasculature, ECs have been widely reported to be impaired during the progression of pulmonary vascular diseases (PVD). Several studies have revealed that KATP play a critical role in pulmonary ECs to shear stress and arterial vasomotion [2, 3]. Knockout of inward rectifier potassium channel 6.1 (Kir6.1), one of the pore-forming subunits of KATP, in the endothelium impaired coronary artery function and elevated blood pressure [4]. KATP have been considered as a crucial controller of ECs

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