Endothelial Overexpression of A Conditional Fas-Induced Apoptosis Construct in Transgenic Mice Triggers Pulmonary Hypertension with Complex Vascular Lesions

Introduction: Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by lung arteriolar remodeling and obliteration. Endothelial cell (EC) apoptosis has been suggested to be an initiating event in PAH, possibly leading to the emergence of highly proliferative, apoptosis resistant vascular cells that contribute to the characteristic plexiform lesions. Therefore, we assessed whether the induction of a defined level of EC apoptosis would be sufficient to produce PAH, as well as proliferative, plexiform-like arteriolar lesions using a novel conditional transgenic mouse model. Methods: The Fas-Induced Apoptosis (FIA) construct contains the cytoplasmic death domain of the Fas receptor together with 2 copies of the FK506-binding peptide (FKBP) domain. This construct was targeted to ECs using the Tie2 promoter in transgenic (i.e. EFIA) mice. Apoptosis was induced by a small molecule dimerizing agent, AP20187, which binds tightly to the FKBP domain, and assessed by TUNEL staining. Right ventricul...