Transgenic mice overexpressing an endothelial‐targeted Fas‐inducing apoptosis construct exhibit pulmonary hypertension associated with marked lung arterial remodeling

Abstract

ObjectivePulmonary 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 ResultsThe Fas‐Induced Apoptosis (FIA) construct was expressed under the control of endothelial‐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.ConclusionOur data suggest that EC apoptosis is sufficient to induce PAH, which is associated with marked inflammation and remodeling of lung arterioles.