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PDGF‐BB signaling in adventitial fibroblasts during hypoxia‐induced pulmonary hypertension
Author(s) -
Panzhinskiy Evgeniy,
Shields Kristin,
Zawada Michael,
Stenmark Kurt,
Das Mita
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.22
Subject(s) - platelet derived growth factor receptor , reactive oxygen species , adventitia , hypoxia (environmental) , platelet derived growth factor , microbiology and biotechnology , superoxide dismutase , phosphorylation , chemistry , endocrinology , biology , medicine , growth factor , receptor , oxidative stress , biochemistry , oxygen , organic chemistry
PDGF‐BB contributes to vascular remodeling during the development of hypoxia‐induced pulmonary hypertension (HPH). Adventitial fibroblasts (AdFibs) are the first cells activated in HPH. We tested the hypothesis that PDGF‐BB‐induced activation of AdFibs is a key regulator of HPH development. Newborn calves were exposed to high altitude (4750 m) (HA) for 2 weeks to induce HPH. Phosphorylated PDGFβ receptor (PDGFβ‐R) levels were markedly elevated in the thickened adventitia of the vessels in HA lungs compared to that of control. PDGFβ‐R expression was similarly activated in AdFib isolated from the main pulmonary artery of HA animals as evaluated by immunoblot analysis. PDGF‐BB stimulated greater proliferation rate and reactive oxygen species (ROS) production in HA cells compared to the AdFibs of control animals. ROS scavengers, N‐Acetyl Cysteine (NAC), and superoxide dismutase mimetic, TEMPOL, selectively inhibited PDGF‐BB‐induced proliferation and ROS production in HA cells. PDGF‐BB induced activation of ERK1/2 and JNK1/2, but not p38 MAP kinase in both cell types. However, both NAC and TEMPOL attenuated PDGF‐BB‐stimulated heightened phosphorylation levels of ERK1/2 and JNK1/2 in HA cells only. Our results suggest that dramatic adventitial remodeling during the progression of HPH depends on PDGF‐BB‐induced AdFib proliferation mediated through ROS production and ERK/JNK MAP kinase activation. Funded by HL64917; P20RR016474