Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling.

Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH. Synopsis: HIF2α signaling plays an important role in the transition of pericytes into smooth muscle cell-like cells in pulmonary hypertension. Hence, targeting HIF2α in pericytes may be a potential therapeutic approach for pulmonary hypertension. Overexpressing HIF2α selectively in pericytes results in vigorous muscularization of distal microvessels and loss of endothelial integrity. Deletion of HIF2α in pericytes alleviates muscularization and remodeling of precapillary arterioles. Lineage tracing of the reporter color labeled cells show that HIF2α overexpressing NG2 cells gain a SMC-like phenotype during disease progression. Inhibition of HIF2α downstream signaling pathways using AMD3100 protects mice from hypoxia induced pulmonary hypertension. HIF2α signaling plays an important role in the transition of pericytes into smooth muscle cell-like cells in pulmonary hypertension. Hence, targeting HIF2α in pericytes may be a potential therapeutic approach for pulmonary hypertension. [ABSTRACT FROM AUTHOR]