Bone Morphogenic Protein-4 Induces Hypertension in Mice

Abstract

Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses. BMP4 infusion by osmotic pumps increased systolic blood pressure in a time- and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E-null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice. These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidase-dependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases.