TGFbeta family member BMP‐2 induces pro‐inflammatory endothelial phenotype

Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a TGFb superfamily member cytokine, is significantly up-regulated in disease-prone vascular beds and atherosclerotic lesions. Despite its pathophysiological importance, the effects of BMP-2 on the endothelium have not been well characterized. We tested the hypothesis that BMP-2 exerts pro-inflammatory effects on endothelial cells. First, we demonstrated mRNA expression of BMP-2 and BMP-4 (a related cytokine) in microdissected coronary arterial endothelial cells and cultured primary coronary arterial endothelial cells (CAECs), which was higher than that in smooth muscle cells. The pro-inflammatory cytokine TNFĄ and H2O2 significantly increased endothelial expression of BMP-2 (but not that of BMP-4). In organ culture, BMP-2 substantially decreased relaxation of rat carotid arteries to acetylcholine and increased production of reactive oxygen species in CAECs and endothelial cells of cultured arteries, which was inhibited by the PKC inhibitor chelerythrine or DPI and apocynin (to block NAD(P)H oxidase). BMP-2 elicited NF-kB activation in CAECs and incubation of carotid arteries with BMP-2 substantially increased adhesion of mononuclear cells to the endothelium. Collectively, expression of BMP-2 is regulated by pro-inflammatory stimuli and increased levels of BMP-2 can induce endothelial dysfunction, oxidative stress and endothelial activation. We propose that the pro-inflammatory endothelial effects of BMP-2 may play a role in vascular pathophysiology. (Grant support: AHA 0430108N, 0435140N, American Federation for Aging Research).