Loss of lung microvascular endothelial Piezo2 expression impairs NO synthesis, induces EndMT and is associated with pulmonary hypertension

Am J Physiol Heart Circ Physiol. 2022 Sep 23. doi: 10.1152/ajpheart.00220.2022. Online ahead of print.ABSTRACTMechanical forces are translated into biochemical stimuli by mechanotransduction channels, such as the mechanically-activated cation channel Piezo2. Lung Piezo2 expression has recently been shown to be restricted to endothelial cells. Hence, we aimed to investigate the role of Piezo2 in regulation of pulmonary vascular function and structure as well as its contribution to development of pulmonary arterial hypertension (PAH). The expression of Piezo2 was significantly reduced in pulmonary microvascular endothelial cells (MVECs) from PAH patients, in lung tissue from mice with a Bmpr2+/R899X knock-in mutation commonly found in pulmonary hypertension patients, and in lung tissue of MCT and SuHx PAH rat models as well as from a swine model with pulmonary vein banding. In MVECs, Piezo2 expression was reduced in response to abnormal shear stress, hypoxia and TGFβ stimulation. Functional studies in MVECs exposed to shear stress illustrated that siRNA-mediated Piezo2 knockdown impaired endothelial alignment, calcium influx, phosphorylation of AKT and nitric oxide production. In addition, siPiezo2 reduced the expression of the endothelial marker PECAM-1 and increased expression of vascular smooth muscle markers ACTA2, SM22a and Calponin. Thus, Piezo2 acts as a mechanotransduction channel in pulmonary MVECs, stimulating shear-induced production of nitric oxide and is essential...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research