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Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations inBMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact ofBMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed.Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients withBMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediatedBMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditionalBmpr2 knockout mice (Bmpr2 EC −/− ). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP targetID1 in the context ofBMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice (Bmpr2 EC+/+ ) but had no measurable effect on mice bearing a heterozygous endothelialBmpr2 deletion (Bmpr2 EC +/−) and caused excessive angiogenesis in both vascular beds forBmpr2 EC −/− mice.Conclusions: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling