The role of apoptosis in a BMPR2 mutant model of pulmonary arterial hypertension

Title: The role of apoptosis in a BMPR2 mutant model of pulmonary arterial hypertension
Authors: Yelle, Dominique
Date: 2011
Abstract: Pulmonary arterial hypertension (PAH) is a rare and fatal disease caused by excessive remodelling of small pulmonary arterioles. Heterozygous loss-of-function mutations in the bone morphogenetic protein receptor 2 (BMPR2) have recently been identified in a large portion of patients with familial and idiopathic PAH. However, how mutations in this ubiquitously expressed receptor result in such a specific abnormality of the lung microcirculation is unknown. We hypothesized that loss-of-function mutations in BMPR2 lead to PAH by increasing the susceptibility of ECs to apoptosis, particularly within fragile pulmonary arterioles. To examine the consequences of BMPR2 mutations on the development of PAH, we generated mice that ubiquitously over-express an arginine to stop mutation in the receptor's C-terminal domain (BMPR2 R899X) Characterization of these mice revealed a significant increase in right ventricular systolic pressure, an indicator of pulmonary pressure, which was associated with muscularization of small pulmonary arterioles, alveolar septal thickening and pulmonary macrophage infiltration. In addition, a modest increase in apoptosis was detected in these mice. These data suggest that BMPR2 loss-of-function mutations increase the susceptibility of ECs to apoptosis and set the stage for excessive inflammation, possibly leading to spontaneous PAH. This new model will help elucidate the pathophysiological events leading to the development of PAH and provide a unique tool to evaluate novel potential treatments for this disease.
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
MR79689.PDF4.33 MBAdobe PDFOpen