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

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 ([Ca 2+ ] 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 [Ca 2+ ] 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.