Deficiency of Endothelial Piezo2 Impairs Pulmonary Vascular Angiogenesis and Predisposes Pulmonary Hypertension

Feng Wei; Ziying Lin; Wenju Lu; Haiyun Luo; Huazhuo Feng; Shiyun Liu; Chenting Zhang; Yulin Zheng; Chen Jiyuan; Shaocong Mo; Chen Wang; Zizhou Zhang; Wei Feng; Junqi Zhu; Qifeng Yang; Min Du; Weiguo Kong; Aofeng Liu; Jiaxuan Lai; Xiang Li; Xuefen Wu; Ning Lai; Yuqin Chen; Kai Yang; Jian Wang

doi:10.1161/HYPERTENSIONAHA.124.22948

Deficiency of Endothelial Piezo2 Impairs Pulmonary Vascular Angiogenesis and Predisposes Pulmonary Hypertension

Hypertension. 2025 Jan 6. doi: 10.1161/HYPERTENSIONAHA.124.22948. Online ahead of print.

Authors

Feng Wei^#¹, Ziying Lin^#¹, Wenju Lu^#¹, Haiyun Luo^#¹, Huazhuo Feng^#¹, Shiyun Liu¹, Chenting Zhang¹, Yulin Zheng¹, Chen Jiyuan², Shaocong Mo¹, Chen Wang¹, Zizhou Zhang¹, Wei Feng¹, Junqi Zhu¹, Qifeng Yang^{1

3}, Min Du^{1

4}, Weiguo Kong¹, Aofeng Liu¹, Jiaxuan Lai¹, Xiang Li^{1

5}, Xuefen Wu¹, Ning Lai¹, Yuqin Chen^#¹, Kai Yang^#¹, Jian Wang^#^{1

3}

Affiliations

¹ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, China. (F.W., Z.L., W.L., H.L., H.F., S.L., C.Z., Y.Z., S.M., C.W., Z.Z., W.F., J.Z., Q.Y., M.D., W.K., A.L., J.L., X.L., X.W., N.L., Y.C., K.Y., J.W.).
² Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (C.J.).
³ Guangzhou National Laboratory, Guangzhou International Bio Island, Guangdong, China (Q.Y., J.W.).
⁴ GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, China. (M.D.).
⁵ Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL (X.L.).

^# Contributed equally.

PMID: 39758000
DOI: 10.1161/HYPERTENSIONAHA.124.22948

Abstract

Background: Mechanosensitive Piezo1 channel plays a key role in pulmonary hypertension (PH). However, the role of Piezo2 in PH remains unclear.

Methods: Endothelial cell (EC)-specific Piezo2 knockout (Piezo2^flox/flox, Tek-Cre⁺; Piezo2^EC-/-) rats and primarily cultured pulmonary microvascular ECs were used to determine the role of Piezo2 in PH.

Results: Data analysis of publicly accessible single-cell RNA-sequencing data sets uncovered significant downregulation of Piezo2 in lung ECs from patients with idiopathic pulmonary arterial hypertension, which was verified in the lungs/ECs from PH rat models induced by hypoxia or monocrotaline. Comparing to wild-type rats, Piezo2^EC^-/- rats exhibited exacerbated PH in both hypoxia-induced PH and monocrotaline-induced PH, characterized by the worsened hemodynamical and histological changes. Piezo2^EC^-/- rats showed dramatic loss of pulmonary microvessels, in association with the decreased intracellular free calcium concentration ([Ca²⁺]_i) and downregulation of VEGFR2 (vascular endothelial growth factor receptor 2) and phosphorylated SRF (serum response factor) in pulmonary microvascular ECs. Knockout of Piezo2 or treatment with a calcium chelator, EDTA, impaired the ability of tube formation and migration in pulmonary microvascular ECs, which was restored by supplementation of extra calcium. A safflower oil diet rich in linoleic acid, which can enhance the stability and function of Piezo2, effectively alleviated PH development in a hypoxia-induced PH rat model.

Conclusions: This study demonstrates that EC-specific knockout of Piezo2 exacerbates PH pathogenesis, at least partially, through the suppression of [Ca²⁺]_i/phosphorylated SRF/VEGFR2 signaling axis in pulmonary vascular ECs. Targeted activation of Piezo2 could be a novel effective strategy for the treatment of PH.

Keywords: angiogenesis; downregulation; endothelial cells; hypertension, pulmonary; microvessels.