Abstract 18658: 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 ventricular systolic pressure (RVSP) and hypertrophy (RV/LV+septal weight) were determined after i.p. injection of the dimerizing agent, AP20187. Immunohistochemistry (IHC) was performed for cell proliferation (Ki67), ECs (CD31, CD34) and inflammatory cells (CD45, CD68).
Results: Administration of AP20187 at 2–10 mg/kg/day for 1 week resulted in a dose-dependent increase in RVSP in EFIA mice only, with significant RV remodeling. AP20187 treatment induced apoptosis in the peripheral lung. Obliterative distal arteriolar lesions were observed at 1 week, in the most severely affected animals. These stained strongly positive for Ki67, consistent with high levels of cell proliferation. Preliminary characterization by IHC revealed that these lesions consisted largely of CD68+ macrophages, and CD31+/CD34+ capillary-like, angioid structures.
Conclusions: These results indicate that EC apoptosis is sufficient to produce PAH associated with proliferative arteriolar lesions that appear to be mainly inflammatory in nature. These findings suggest that EC apoptosis may trigger an innate immune response in the lung, and this new model could provide insight into the genesis of plexiform arteriopathy seen typically in patients with advanced PAH.
- © 2010 by American Heart Association, Inc.