Abdul Q. Sheikh, Ralf H. Adams and Daniel M. Greif
Yale Cardiovascular Research Center, Yale University, USA
Excess and ectopic smooth muscle cells (SMCs) are central to cardiovascular disease pathogenesis, but underlying mechanisms are poorly defined. For instance, pulmonary hypertension (PH) or elevated pulmonary artery blood pressure is a lethal disease with distal extension of smooth muscle to normally unmuscularized pulmonary arterioles. We recently demonstrated that embryonic pulmonary artery wall morphogenesis consists of discrete developmentally regulated steps. In contrast, poor understanding of distal arteriole muscularization in pulmonary artery hypertension severely limits existing therapies that aim to dilate the pulmonary vasculature but have modest clinical benefit and do not prevent hypermuscularization. Here, we show that most pathological distal arteriole smooth muscle cells derive from pre-existing smooth muscle and the program of distal arteriole muscularization encompasses smooth muscle cell dedifferentiation, distal migration, proliferation, and then redifferentiation. Interestingly, we consistently detect a few SMA+SMMHC+PDGFR-β+ cells adjacent to the arteriole muscularunmuscular transition in normoxia and these cells are primed to dedifferentiate, migrate and colonially expand in hypoxia-induced PH. In sum, novel SMC progenitors are critical for the pathogenesis of PH, and perhaps other vascular disorders, and therapeutic strategies targeting this cell type have profound implications.