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

OBJECTIVE

Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in -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 of 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 with mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional knockout mice (). 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 target in the context of loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice () but had no measurable effect on mice bearing a heterozygous endothelial deletion () and caused excessive angiogenesis in both vascular beds for mice.

CONCLUSIONS

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.