Abstract 17070: Bmpr1a and Its Role in Endomt in Pulmonary Arterial Hypertension

Abstract

There is emerging evidence that the aberrant pulmonary vascular remodeling that occurs in pulmonary arterial hypertension (PAH) is at least in part driven by the transformation of endothelial cells to mesenchymal cells (EndoMT), but the mechanism driving this pathobiology remains to be fully elucidated. Bone morphogenetic protein (BMP) signaling has been implicated to be involved in EndoMT in different vascular contexts, but the exact mechanism in the pulmonary vasculature remains to be defined. We describe the role of BMP receptor type 1A (BMPR1A or ALK3) as a key factor for maintenance of endothelial fate and suppression of EndoMT in the pulmonary vasculature. We found that inducible endothelial specific deletion of Bmpr1a in mice ( Bmpr1a iECKO ) resulted in spontaneous EndoMT, with significant increase in smooth muscle actin (SMA) positive cells, associated with extensive pulmonary vascular remodeling and fibrosis. Bmpr1a iECKO mice developed spontaneous pulmonary hypertension (PH) that was mediated by augmented TGF-β signaling driven by increased TGFBR2 expression, resulting in aberrant SMAD2/3 activation. Increased TGFBR2 expression in BMPR1A deficient state was secondary to increased activity of the transcription factor TCF3, whose negative inhibition by ID2 is abrogated in BMPR1A deficient state. EndoMT and PH secondary to loss of endothelial BMPR1A was effectively rescued by concurrent knockdown of TGFBR2. Overall, these studies define a mechanism of EndoMT driven by loss of endothelial BMPR1A, and demonstrate the efficacy of inhibiting EndoMT as a potential novel therapeutic strategy in PAH and other EndoMT-related vascular disorders.