title: Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: a process mediated by hypoxia and endothelin-1.
abstract: The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.
authors.affiliation: Department of Pediatric Cardiology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box C218, Denver, CO 80262, USA. neil.davie@uchsc.edu
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Davie
authors.forename: Evgenia V
authors.initials: EV
authors.lastname: Gerasimovskaya
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Hofmeister
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Richman
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jones
authors.forename: John T
authors.initials: JT
authors.lastname: Reeves
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D002417:Cattle; D018929:Cell Culture Techniques / Q000379:methods; D049109:Cell Proliferation; D002478:Cells, Cultured / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005347:Fibroblasts / Q000473:pathology*; D006973:Hypertension / Q000473:pathology; D000860:Hypoxia; D008856:Microscopy, Fluorescence; D011651:Pulmonary Artery / Q000378:metabolism*
chemical_list: D019332:Endothelin-1