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Transgenic mice overexpressing an endothelial‐targeted Fas‐inducing apoptosis construct exhibit pulmonary hypertension associated with marked lung arterial remodeling
Author(s) -
Goldthorpe Heather,
Parsons Sean A.,
Jiang Jin-Yi,
Deng Yupu,
Stewart Duncan J.
Publication year - 2012
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.26.1_supplement.143.3
Subject(s) - apoptosis , lung , genetically modified mouse , transgene , pulmonary hypertension , pathology , medicine , inflammation , vascular remodelling in the embryo , endocrinology , chemistry , biochemistry , gene
Objective Pulmonary arterial hypertension (PAH) is a lethal disease, characterized by complex vascular lesions and increased pulmonary vascular resistance. To test the hypothesis that lung EC apoptosis at the level of distal pulmonary arterioles is necessary and sufficient to cause PAH phenotype we developed a novel transgenic model. Methods and Results The F as‐ I nduced A poptosis (FIA) construct was expressed under the control of e ndothelial‐specific, Tie2 promoter in transgenic mice (i.e. EFIA mice). Two transgenic lines characterized by low and high expression levels (LE and HE, respectively) were generated. LE‐EFIA exhibited normal pulmonary hemodynamics and vascular structure at baseline; however, administration of a small molecule dimerizing agent, AP20187, resulted in lung microvascular apotosis and modest dose‐dependent increase in RVSP. Interestingly, HE‐EFIA transgenic mice showed significant elevation in baseline RVSP compared to wild‐type controls even in the absence of the AP compound (34± vs. 24±4 mm Hg, respectively; p<0.005). 40% of HE‐EFIA mice also exhibited perivascular lesions, localized to distal lung arterioles which were highly proliferative by Ki67 and EDU staining, and exhibited variable degrees of apoptosis. Conclusion Our data suggest that EC apoptosis is sufficient to induce PAH, which is associated with marked inflammation and remodeling of lung arterioles.