Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension

Abstract

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.

Resident PW1 + Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension

“…Although this is not a bona fide lineage-tracing model, the long half-life of β-gal protein 21 (and our own in vitro data) + cells represent 50% of all the proliferating cells found in the lung parenchyma after 4 days of CH (data not shown). Therefore, altogether our results with previous ones 5,7 suggest that hypoxia-induced pulmonary vessels muscularization is dependent on multiple resident SMC sources recruited successively: PW1 + /CD34 + progenitor cells, PDGFR-β + SMC, and NG2 + pericytes. Other investigations have also reported significant recruitment of resident perivascular progenitor cells during vascular remodeling/pathophysiology such as the restenosis 33 or the atherosclerosis.…”

PBX transcription factors drive pulmonary vascular adaptation to birth

“…To determine the mechanism underlying the severe PH observed in Pbx1/2-CKO mutants, we investigated possible causes including decreased lung vessel number and size, VSM hypertrophy, and ectopic placement of VSM on distal pulmonary arterioles (36)(37)(38). At P7, when PH was detected by the PAAT/PAET ratio, we detected no statistically significant reduction in the number of vessels outlined by vWF staining (Figure 3 (Figure 3I).…”

Catching a Disease: A Molecular Trap as a Therapy for Pulmonary Arterial Hypertension

“…Smooth muscle cells coat arterioles in the proximal and middle, but not distal, lung; however, hypoxia induces distal arteries to muscularize, which is a hallmark of PAH. Murine lineage tracking models have identified a role for smooth muscle cells located adjacent to unmuscularized regions in PAH remodeling (13). These cells coexpress smooth muscle cell differentiation and mesenchymal markers; in response to hypoxia, they turn on the pluripotency transcription factor, KLF4; lose their fully differentiated contractile phenotype; proliferate; and migrate to distal vessels (13).…”

“…Murine lineage tracking models have identified a role for smooth muscle cells located adjacent to unmuscularized regions in PAH remodeling (13). These cells coexpress smooth muscle cell differentiation and mesenchymal markers; in response to hypoxia, they turn on the pluripotency transcription factor, KLF4; lose their fully differentiated contractile phenotype; proliferate; and migrate to distal vessels (13). Interestingly, KLF4 promotes histone acetylation on TGF-b1 target genes (14), suggesting KLF4-enhanced TGF-b1 signaling might drive dedifferentiation and proliferation of these smooth muscle cells and promote distal muscularization in PAH.…”