title: Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall.
abstract: All forms of chronic pulmonary hypertension (PH) are characterized by structural remodeling of the pulmonary artery (PA) media, a process previously attributed solely to changes in the phenotype of resident smooth muscle cells (SMC). However, recent experimental evidence in both systemic and pulmonary circulations suggests that other cell types, including circulating and local progenitors, contribute significantly to this process. The goal of this study was to determine if hypoxia-induced remodeling of distal PA (dPA) media involves the emergence of cells with phenotypic and functional characteristics distinct from those of resident dPA SMC and fibroblasts. In vivo, in contrast to the phenotypically uniform SMC composition of dPA media in control calves, the remodeled dPA media of neonatal calves with severe hypoxia-induced PH comprised cells exhibiting a distinct phenotype, including the expression of hematopoetic (CD45), leukocytic/monocytic (CD11b, CD14), progenitor (cKit), and motility-associated (S100A4) cell markers. Consistent with these in vivo observations, primary cell cultures isolated from dPA media of hypertensive calves yielded not only differentiated SMC, but also smaller, morphologically rhomboidal (thus termed here "R") cells that transiently expressed CD11b, constitutively expressed the mesenchymal cell marker type I procollagen, expressed high mRNA levels of progenitor cell markers cKit, CD34, CD73, as well as for inflammatory mediators, IL-6 and MCP-1, and, with time in culture, gained expression of a myofibroblast marker, alpha-SM-actin. R cells exhibited highly augmented proliferative, migratory, invasive, and potent promitogenic capabilities, which were due, at least in part, to the production of PDGFs, SDF-1/CXCL12, and S100A4. These data suggest that the cellular mechanisms of dPA remodeling include the emergence of cells with phenotypic and functional characteristics markedly distinct from those of resident dPA cells.
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, 80045, USA. Maria.Frid@ucdenver.edu
authors.forename: Maria G
authors.initials: MG
authors.lastname: Frid
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Meena
authors.initials: M
authors.lastname: Gnanasekharan
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Burke
authors.forename: Miguel
authors.initials: M
authors.lastname: Fragoso
authors.forename: Derek
authors.initials: D
authors.lastname: Strassheim
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Sylman
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D015415:Biomarkers / Q000378:metabolism; D002417:Cattle; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D003470:Culture Media; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000473:pathology; D000860:Hypoxia / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism*; D019899:Paracrine Communication; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D054377:Chemokine CXCL12; D003470:Culture Media; D018836:Inflammation Mediators; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C499413:S100A4 protein, Bos taurus