title: 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.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Room 773J, New Haven, CT 06511, USA.
authors.forename: Abdul Q
authors.initials: AQ
authors.lastname: Sheikh
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Room 773J, New Haven, CT 06511, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Misra
authors.affiliation: Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, and Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Room 773J, New Haven, CT 06511, USA. daniel.greif@yale.edu.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Greif
mesh_terms: D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors