Csiszar Anna, Labinskyy Nazar, Jo Hanjoong, Ballabh Praveen, Ungvari Zoltan
Dept. of Physiology, New York Medical College, Valhalla, New York 10595, USA.
Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H569-77. doi: 10.1152/ajpheart.00180.2008. Epub 2008 Jun 6.
There is increasing evidence that TGF-beta family member cytokine bone morphogenetic protein (BMP)-4 plays different pathophysiological roles in the pulmonary and systemic circulation. Upregulation 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 the pulmonary and systemic circulation, we compared the prooxidant and proinflammatory 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 O(2)(-) and H(2)O(2) generation, induced NF-kappaB activation, upregulated ICAM-1, and induced monocyte adhesiveness to ECs. In contrast, BMP-4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP-4 treatment impaired acetylcholine-induced relaxation and increased O(2)(-) 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 prooxidant, prohypertensive, and proinflammatory 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.
越来越多的证据表明，转化生长因子-β家族成员细胞因子骨形态发生蛋白（BMP）-4在肺循环和体循环中发挥着不同的病理生理作用。BMP-4的上调与体循环中的动脉粥样硬化和高血压有关，而BMP-4信号的破坏与肺动脉高压的发展相关。为了验证BMP-4在肺循环和体循环中产生不同作用的假说，我们比较了BMP-4在培养的人冠状动脉内皮细胞（CAEC）和肺动脉内皮细胞（PAEC）中的促氧化和促炎作用。我们发现，CAEC中BMP-4（0.3至10 ng/ml）可增加超氧阴离子（O₂⁻）和过氧化氢（H₂O₂）的生成，诱导核因子κB（NF-κB）激活，上调细胞间黏附分子-1（ICAM-1），并诱导单核细胞与内皮细胞的黏附。相反，BMP-4未能在PAEC中诱导氧化应激或内皮细胞激活。此外，BMP-4处理损害了培养的大鼠颈动脉中乙酰胆碱诱导的舒张，并增加了超氧阴离子的产生，而培养的大鼠肺动脉则免受BMP-4的这些不利影响。因此，我们提出BMP-4仅在体循环中发挥促氧化、促高血压和促炎作用，而肺动脉免受BMP-4的这些不利影响。BMP-4在血管床特异性的内皮细胞作用可能有助于其在体循环和肺循环中不同的病理生理作用。
