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Coordinate activation of cardiac and pulmonary fibroblasts by hypoxia‐induced pulmonary hypertension in a transgenic mouse model
Author(s) -
Brown R. Dale,
Ambler S. Kelly,
Stenmark Kurt R.
Publication year - 2009
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.23.1_supplement.1002.11
Subject(s) - fibroblast , green fluorescent protein , myofibroblast , transgene , pulmonary hypertension , ventricle , hypoxia (environmental) , genetically modified mouse , microbiology and biotechnology , lung , biology , pathology , chemistry , medicine , cell culture , gene , fibrosis , biochemistry , genetics , organic chemistry , oxygen
Activation of adventitial fibroblasts and myofibroblasts is an important determinant of pulmonary vascular remodeling in hypoxia‐induced pulmonary hypertension (PH). PH leads to right ventricular hypertrophy and failure. We hypothesized that hypoxia activates cardiac fibroblasts in concert with pulmonary fibroblasts. Transgenic mice expressing fibroblast phenotype‐sensitive promoter:reporter constructs (Collagen I promoter:Enhanced Green Fluorescent Protein, Coll I:EGFP; fibroblast phenotype; Smooth Muscle alpha‐Actin promoter:Red Fluorescent Protein, SMA:RFP, myofibroblast phenotype) were exposed to hypobaric hypoxia (6 weeks, 10% pO 2 ). Fibroblast activation was monitored by reporter fluorescence in frozen tissue sections and by FACS analysis of enzymatically dispersed cells. Hypoxic exposure significantly elevated cardiac expression of SMA:RFP with a modest enhancement of CollI:EGFP. Increased RFP expression was greatest in right ventricle. Increased expression of RFP and EGFP were also observed in perivascular and parenchymal regions of lung. Distinct lung cell populations expressing fluorescent reporter proteins were observed by FACS analysis (EGFP+ > RFP+EGFP+ > RFP+). Coordinate activation of cardiac and pulmonary fibroblasts in response to hypoxia offers opportunities for novel fibroblast‐targeted therapies in PH. Supported by NIH HL014985.