Specialized Smooth Muscle Cell Progenitors in Pulmonary Hypertension

The accumulation of excessive and ectopic smooth muscle cells (SMCs) is integral to the pathogenesis of diverse cardiovascular diseases, including atherosclerosis, restenosis and pulmonary hypertension. Unfortunately, underlying mechanisms are poorly understood which markedly limits therapeutic options. In the idiopathic form of pulmonary hypertension, reduced pulmonary artery compliance is a strong independent predictor of mortality (Mahapatra et al. J Am Coll Cardiol 47(4):799–803, 2006). Distal arteriole endothelial tubes in the normal lung lack a SMC coating, and pathological distal arteriole muscularization contributes to the reduced compliance. Recently, we identified specialized progenitors that are located at the muscular-unmuscular border of each arteriole in the normal lung and express markers of SMCs and the undifferentiated mesenchyme marker platelet-derived growth factor receptor-β (Sheikh et al. Cell Rep 6(5):809–17, 2014; Sci Transl Med 7(308):308ra159, 2015). Upon exposing mice to hypoxia, these “primed” SMC progenitors are induced to express the pluripotency factor Kruppel-like factor 4 (Sheikh et al. Sci Transl Med 7(308):308ra159, 2015). Subsequently, one of these primed cells migrates distally and in a cell autonomous hypoxia-inducible factor (HIF)1-α-dependent manner and clonally expands, giving rise to distal arteriole SMCs (Sheikh et al. Sci Transl Med 7(308):308ra159, 2015; Cell Rep 23(4):1152–65, 2018). Additionally, endothelial cell HIF1-α-dependent signaling contributes in a non-cell autonomous manner, regulating induction, proliferation and differentiation of primed cells (Sheikh et al. Cell Rep 23(4):1152–65, 2018).