There is increasing evidence that TGF family member cytokine bone morphogenetic protein-4 (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 (from 0.3 to 10 ng/mL) in CAECs increased O₂^.- and H₂O₂ generation, induced NF-B activation, up-regulated ICAM-1 and induced monocyte adhesiveness to endothelial cells. In contrast, BMP-4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP-4 treatment impaired acetylcholine-induced relaxation and increased O₂^.- production in cultured rat carotid arteries, whereas cultured rat pulmonary arteries were protected from these adverse effects of BMP-4. Thus, we propose that 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.