Lingli Wang MD, Jan Renier Moonen MD, PhD, Aiqin Cao PhD, Caiyun G Li PhD, Nesrine El-Bizri PhD, Pin-I Chen PhD, Nancy Ferreira Tojais PhD, Hirofumi Sawada MD, PhD, YuMee Kim PhD, Marlene Rabinovitch MD
Department of Pediatrics (Cardiology), & Cardiovascular Institute, Stanford University, School of Medicine, Stanford, CA
Mutations in bone morphogenetic protein receptor 2 (BMPR2) are associated with idiopathic pulmonary arterial hypertension (PAH), but the link between loss of BMPR2 and the pathogenesis of PAH remains unclear. To understand the role of BMPR2, we generated mice lacking BMPR2 in vascular smooth muscle cells (SMC) with reporter (SM22 Cre+R26R+Bmpr2-/-). The penetrance of a ventricular septal defect was 50%. SM22 Cre-Bmpr2-/- survivors were compared to controls in room air, three weeks of hypoxia and following four weeks recovery in room air (n = 4-8). While female groups were similar under all conditions, mutant males showed reduced hypoxia-induced vasoconstriction and developed less severe PH following chronic hypoxia, judged by right ventricular systolic pressure. There was, however, more persistent PH following recovery, associated with sustained muscularization of distal pulmonary arteries (PA). We found that PASMCs from male SM22 Cre-Bmpr2-/- mice vs. controls were less contractile in response to angiotensin II (4μM) and showed heightened proliferation and resistance to apoptosis. We observed a similar phenotype in human PASMC where BMPR2 was knocked down by siRNA, related to increased ꞵ-arrestin2 and active ꞵ-catenin and reduced active RhoA and Rac1. Reducing ꞵ-arrestin2 restored the contractile phenotype and attenuated the heightened proliferation phenotype. Interestingly, tissue staining revealed heightened expression of ꞵ-arrestin2 and active ꞵ-catenin in PASMCs of PAH patients with BMPR2 mutation vs. controls. Our study relates loss of BMPR2 in PASMC to impaired PA contractility and heightened PASMC proliferation. The mechanism is consistent with dysregulation of tandem ꞵ-catenin and RhoA signaling in response to BMPR2 stimulation.