Bone morphogenetic protein‐2 and ‐4 increase monocyte adhesiveness to the endothelium via a ERK1/2‐dependent pathway

Abstract

The TGFβ superfamily member cytokines, bone morphogenetic protein-2 (BMP-2) and -4 have been linked to the development of atherosclerotic lesions. Because the pathomechanisms by which BMPs affect the function of blood vessels are less understood, we tested the effect of BMPs on endothelial activation. BMP-2 and BMP-4 significantly increased monocyte adherence to cultured human coronary arterial endothelial cells (HCAECs). Pre-treatment of the vessels with pharmacological inhibitors of PKC, p38 and p42/44 MAP kinases, and NAD(P)H oxidase (DPI, apocynin) significantly reduced or prevented BMP-2 and BMP-4 induced monocyte adhesion. Pre-treatment of HCAECs with anti-p42/44 MAP kinase siRNAs prevented BMP-2 induced increases in monocyte adhesiveness. Both in carotid arterial segments and HCAECs BMP-2 elicited rapid increases in phosphorylation of p42/44 MAP kinase. BMP-2 induced phosphorylation of p42/44 MAP kinase was decreased in HCAECs pre-treated with DPI and chelerythrine. Thus, we propose that BMP-2 and -4 activate MAP kinase pathways in the endothelium, which promotes monocyte adhesiveness. BMP-2/4 induced endothelial activation is likely to underlie the association of BMP expression with atherogenesis. (Grant support: AHA 0430108N, 0435140N, American Federation for Aging Research, AHAF H2004-024).