We are pleased to announce the awardees of the PVRI BMPR2 Research Grants supported by the Dinosaur Trust. These two winners were selected out of 12 very competitive applications. The applications were peer-reviewed by the PVRI Grants Advisory Committee, which includes international specialists in the field of pulmonary arterial hypertension.
The two winners are:
Sebastien Bonnet, Professor in Medicine, University of Laval, Canada, & Frederic Perros, INSERM U999 – University of Paris-Sud, France
Pulmonary arterial hypertension (PAH) is a devastating disease characterised by a progressive increase of arterial blood pressure in the lungs. Endothelial cells (EC) dysfunction and aberrant proliferation of pulmonary arterial smooth muscle cells (PASMC) contribute to a progressive obliteration of the precapillary vessels that leads to increased pulmonary arterial pressure and ultimately, right heart failure and death.
Among identified molecular factors that promote PAH, the alteration of the BMPR2 signalling pathways seems to play a key role in the pathogenesis. Mutations on the BMPR2 gene are the main genetic risk factors for PAH and are found in 75% of familial and 20% of idiopathic PAH. Nevertheless, the average penetrance of PAH among the mutation carriers is low (20%), thus suggesting that other triggers are necessary to initiate PAH pathogenesis. Because 94% of patients with pulmonary hypertension due to heart diseases and 34% of patients with idiopathic PAH display at least 2 characteristics of metabolic syndrome, and as the decrease in BMPR2 signalling alter metabolism we hypothesised that BMPR2 deficient signalling may worsen metabolic disorders that in return act as the second trigger that worsen PAH development.
Hyung Chun, Associate Professor of Medicine, Section of Cardiovascular Medicine, Yale School of Medicine, USA
Pulmonary arterial hypertension is a rare disease with the hallmark of vascular remodelling of the pulmonary arterioles. Although our understanding of the signalling perturbations in the disease paradigm has advanced, the translational advancement of these findings has been limited, as reflected upon the limited number of drug targets currently utilised in the clinical setting. A key signalling paradigm that has been demonstrated to underlie both the clinical context and experimental models is that mediated by Bone Morphogenetic Protein Receptor Type 2 (BMPR2). We recently defined a key, previously undefined interaction between BMPR2 and Vascular Endothelial Growth Factor Receptor 3 (VEGFR3 or FLT4) that provides a novel paradigm for endothelial BMP signaling. In our studies, generously supported by the PVRI Dinosaur Trust BMPR2 grant, we will elucidate the VEGFR3-BMPR2 interaction by characterising the key molecular domains that are critical to the VEGFR3-BMPR2 association as a key regulatory mechanism of BMPR2 function. Moreover, we will demonstrate the significance of VEGFR3-BMPR2 interaction in vivo using genetic and experimental models of PH, using mice with endothelial specific Vegfr3 and Bmpr2 deletions, as well as delivery of VEGFR3 coding messenger RNA to the lungs using lung endothelial targeting nanotechnology.