title: Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension.
abstract: Increased cell proliferation and migration, of several cell types are key components of vascular remodeling observed in pulmonary hypertension (PH). Our previous data demonstrate that adventitial fibroblasts isolated from pulmonary arteries of chronically hypoxic hypertensive calves (termed PH-Fibs) exhibit a "constitutively activated" phenotype characterized by high proliferative and migratory potential. Osteopontin (OPN) has been shown to promote several cellular activities including growth and migration in cancer cells. We thus tested the hypothesis that elevated OPN expression confers the "activated" highly proproliferative and promigratory/invasive phenotype of PH-Fibs. Our results demonstrate that, both in vivo and ex vivo, PH-Fibs exhibited increased expression of OPN, as well as its cognate receptors, α(V)β(3) and CD44, compared with control fibroblasts (CO-Fibs). Augmented OPN expression in PH-Fibs corresponded to their high proliferative, migratory, and invasive properties and constitutive activation of ERK1/2 and AKT signaling. OPN silencing via small interfering RNA or sequestering OPN production by specific antibodies led to decreased proliferation, migration, invasion, and attenuated ERK1/2, AKT phosphorylation in PH-Fibs. Furthermore, increasing OPN levels in CO-Fibs via recombinant OPN resulted in significant increases in their proliferative, migratory, and invasive capabilities to the levels resembling those of PH-Fibs. Thus our data suggest OPN as an essential contributor to the activated (highly proliferative, migratory, and proinvasive) phenotype of pulmonary adventitial fibroblasts in hypoxic PH.
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Adil
authors.initials: A
authors.lastname: Anwar
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Maria G
authors.initials: MG
authors.lastname: Frid
authors.forename: Binod
authors.initials: B
authors.lastname: Kumar
authors.forename: Evgenia V
authors.initials: EV
authors.lastname: Gerasimovskaya
authors.forename: Suzette R
authors.initials: SR
authors.lastname: Riddle
authors.forename: B Alexandre
authors.initials: BA
authors.lastname: McKeon
authors.forename: Roopa
authors.initials: R
authors.lastname: Thukaram
authors.forename: Barbara O
authors.initials: BO
authors.lastname: Meyrick
authors.forename: Mehdi A
authors.initials: MA
authors.lastname: Fini
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D002417:Cattle; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009361:Neoplasm Invasiveness; D053495:Osteopontin / Q000097:blood / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D018960:Hyaluronan Receptors; D039302:Integrin alphaVbeta3; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt