title: High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization.
abstract: Angiogenic expansion of the vasa vasorum (VV) is an important contributor to pulmonary vascular remodeling in the pathogenesis of pulmonary hypertension (PH). High proliferative potential endothelial progenitor-like cells have been described in vascular remodeling and angiogenesis in both systemic and pulmonary circulations. However, their role in hypoxia-induced pulmonary artery (PA) VV expansion in PH is not known. We hypothesized that profound PA VV neovascularization observed in a neonatal calf model of hypoxia-induced PH is due to increased numbers of subsets of high proliferative cells within the PA adventitial VV endothelial cells (VVEC). Using a single cell clonogenic assay, we found that high proliferative potential colony-forming cells (HPP-CFC) comprise a markedly higher percentage in VVEC populations isolated from the PA of hypoxic (VVEC-Hx) compared with control (VVEC-Co) calves. VVEC-Hx populations that comprised higher numbers of HPP-CFC also demonstrated markedly higher expression levels of CD31, CD105, and c-kit than VVEC-Co. In addition, significantly higher expression of CD31, CD105, and c-kit was observed in HPP-CFC vs. the VVEC of the control but not of hypoxic animals. HPP-CFC exhibited migratory and tube formation capabilities, two important attributes of angiogenic phenotype. Furthermore, HPP-CFC-Co and some HPP-CFC-Hx exhibited elevated telomerase activity, consistent with their high replicative potential, whereas a number of HPP-CFC-Hx exhibited impaired telomerase activity, suggestive of their senescence state. In conclusion, our data suggest that hypoxia-induced VV expansion involves an emergence of HPP-CFC populations of a distinct phenotype with increased angiogenic capabilities. These cells may serve as a potential target for regulating VVEC neovascularization.
authors: Univ. of Colorado Denver, Pediatric Critical Care Medicine, Box B131, Research 2, Rm. 6119, 12700 E. 19th Ave., Aurora, CO 80045. evgenia.gerasimovskaya@ucdenver.edu.
authors: Hala
authors: H
authors: Nijmeh
authors: Vivek
authors: V
authors: Balasubramaniam
authors: Nana
authors: N
authors: Burns
authors: Aftab
authors: A
authors: Ahmad
authors: Kurt R
authors: KR
authors: Stenmark
authors: Evgenia V
authors: EV
authors: Gerasimovskaya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D002417:Cattle; D054443:Cell Migration Assays; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology*; D019098:Telomerase / Q000378:metabolism; D014651:Vasa Vasorum / Q000503:physiopathology*
chemical_list: D015703:Antigens, CD; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019009:Proto-Oncogene Proteins c-kit; D019098:Telomerase
keywords: endothelial clusters; endothelial progenitor cells; high proliferative potential endothelial colony-forming cells; pulmonary hypertension; vascular remodeling