Differential Pro‐inflammatory/Pro‐oxidant Effects of BMP‐4 in Coronary and Pulmonary Arterial Endothelial Cells

Abstract

There is increasing evidence that TGF£] family member cytokine BMP‐4 plays different pathophysiological roles in the pulmonary and systemic circulation. Up‐regulation of BMP‐4 has been linked to atherosclerosis and hypertension in the systemic circulation, whereas disruption of BMP‐4 signaling is associated with the development of pulmonary hypertension. To test the hypothesis that BMP‐4 elicits differential effects in pulmonary and systemic circulation, we compared the pro‐oxidant and pro‐inflammatory effects of BMP‐4 in cultured human coronary arterial endothelial cells (CAECs) and pulmonary arterial endothelial cells (PAECs). We found that BMP‐4 in CAECs increased O2.‐ and H2O2 generation, induced NF‐ f;ÛB activation, up‐regulated ICAM‐1 and induced monocyte adhesiveness. In contrast, BMP‐4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP‐4 treatment impaired ACh‐induced relaxation and increased O2.‐ production only in cultured rat carotid (but not pulmonary) arteries. Thus, BMP‐4 exerts pro‐oxidant, pro‐hypertensive and pro‐inflammatory effects only in the systemic circulation, whereas pulmonary arteries are protected from these adverse effects of BMP‐4. The vascular bed‐specific endothelial effects of BMP‐4 are likely to contribute to its differential pathophysiological role in the systemic and pulmonary circulation.