Research ArticlePulmonary Hypertension

Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension

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Science Translational Medicine  07 Oct 2015:
Vol. 7, Issue 308, pp. 308ra159
DOI: 10.1126/scitranslmed.aaa9712

A smooth transition in pulmonary hypertension

Recently, researchers sought to explain the incredible growth rate of the superheroes the Incredible Hulk and Captain America. Although no “super-soldier serum” exists, they decided it might be possible to recreate such a rapid increase in muscle mass through gene editing, but ultimately, the transformation could be “traumatic.” In a real-life situation, Sheikh and colleagues similarly investigated how the overgrowth of smooth muscle in the vasculature happens in pulmonary hypertension, with the hopes of targeting this process and preventing the onset of PH—a disease with few therapeutic options. In PH, normally unmuscularized tissue becomes muscularized, likely due to low oxygen (hypoxia). The authors used a series of genetic mouse models to characterize a unique cell type that expressed a smooth muscle cell (SMC) marker and platelet-derived growth factor receptor-β (PDGFR-β), and reside at the border zone of muscle and nonmuscle in the pulmonary arterioles. Knowing that these precursor cells are “primed” to become arteriole SMCs, Sheikh et al. tracked the cells over time, in living mice, during hypoxia-induced PH and discovered that the SMCs expanded clonally (from a single, specialized cell). Human pulmonary artery SMCs expressed high levels of a factor known as KLF4, which is downstream in PDGF signaling. Back in the mice, the authors found that KLF4 was required by the SMCs to migrate distally and “muscularize.” This novel SMC precursor therefore plays a major role in PH, and—perhaps much to the benefit of our favorite superheroes’ enemies—targeting the now-clear mechanisms of SMC migration and proliferation could prevent the characteristic muscular transition in disease.


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 devastating disease with distal extension of smooth muscle to normally unmuscularized pulmonary arterioles. We identify novel SMC progenitors that are located at the pulmonary arteriole muscular-unmuscular border and express both SMC markers and the undifferentiated mesenchyme marker platelet-derived growth factor receptor-β (PDGFR-β). We term these cells “primed” because in hypoxia-induced PH, they express the pluripotency factor Kruppel-like factor 4 (KLF4), and in each arteriole, one of them migrates distally, dedifferentiates, and clonally expands, giving rise to the distal SMCs. Furthermore, hypoxia-induced expression of the ligand PDGF-B regulates primed cell KLF4 expression, and enhanced PDGF-B and KLF4 levels are required for distal arteriole muscularization and PH. Finally, in PH patients, KLF4 is markedly up-regulated in pulmonary arteriole smooth muscle, especially in proliferating SMCs. In sum, we have identified a pool of SMC progenitors that are critical for the pathogenesis of PH, and perhaps other vascular disorders, and therapeutic strategies targeting this cell type promise to have profound implications.

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