Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling
Hyunbum Kim, Yu Liu, Jiwon Kim, Yunhye Kim, Timothy Klouda, Sudeshna Fisch, Seung Han Baek, Tiffany Liu, Suzanne E. Dahlberg, Cheng‐Jun Hu, Wen Tian, Xinguo Jiang, Kosmas Kosmas, Helen Christou, Benjamin D. Korman, Sara O. Vargas, Joseph C. Wu, Kurt R. Stenmark, Vinicio de Jesús Pérez, Mark R. Nicolls, Benjamin A. Raby, Ke Yuan
Abstract
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.