Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension

Abstract

Summary: Pulmonary hypertension is a devastating disease characterized by excessive vascular muscularization. We previously demonstrated primed platelet-derived growth factor receptor β+ (PDGFR-β+)/smooth muscle cell (SMC) marker+ progenitors at the muscular-unmuscular arteriole border in the normal lung, and in hypoxia-induced pulmonary hypertension, a single primed cell migrates distally and expands clonally, giving rise to most of the pathological smooth muscle coating of small arterioles. Little is known regarding the molecular mechanisms underlying this process. Herein, we show that primed cell expression of Kruppel-like factor 4 and hypoxia-inducible factor 1-α (HIF1-α) are required, respectively, for distal migration and smooth muscle expansion in a sequential manner. In addition, the HIF1-α/PDGF-B axis in endothelial cells non-cell autonomously regulates primed cell induction, proliferation, and differentiation. Finally, myeloid cells transdifferentiate into or fuse with distal arteriole SMCs during hypoxia, and Pdgfb deletion in myeloid cells attenuates pathological muscularization. Thus, primed cell autonomous and non-cell autonomous pathways are attractive therapeutic targets for pulmonary hypertension. : Sheikh et al. demonstrate that hypoxia-induced expression of KLF4 and HIF1-α in specialized lung arteriole SMC progenitors is required for distal migration and smooth muscle expansion, respectively. A HIF1-α/PDGF-B axis in endothelial cells non-cell autonomously regulates progenitor SMC induction, proliferation, and differentiation. The myeloid cell lineage marks SMCs. Keywords: smooth muscle biology, vascular wall, vascular biology, pulmonary artery, pulmonary hypertension, pulmonary vascular disease, vasculoproliferative disease, cardiovascular disease, endothelial-smooth muscle cell interactions, smooth muscle progenitors