Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells
Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells
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DOI：
10.1074/jbc.m109.002881
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发表时间：
2009-06-05
影响因子：
4.8
通讯作者：
Morrell, Nicholas W.
中科院分区：
文献类型：
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作者：
Upton, Paul D.;Davies, Rachel J.;Morrell, Nicholas W.
转化生长因子-β（TGF-β）受体超家族成员的突变是以血管发育不良为特征的疾病的基础。内皮糖蛋白和激活素样激酶受体1（ALK 1）突变引起遗传性出血性毛细血管扩张症，而骨形态发生蛋白II型受体（BMPR-II）突变是家族性肺动脉高压的基础。为了了解这些受体的功能作用，我们研究了它们对人肺动脉内皮细胞（HPAECs）中BMP信号传导的相对贡献。BMP 9可有效地选择性诱导HPAEC中Smad 1/5磷酸化和Id基因表达。与预期相反，BMP 9也刺激Smad 2激活。此外，BMP 9诱导白细胞介素8和E-选择素的表达。使用小干扰RNA，我们证明了I型受体ALK 1对这些反应至关重要。然而，小干扰RNA和抑制剂研究显示不涉及ALK 5或内皮糖蛋白。我们进一步证明，候选II型受体，BMPR-II主要介导的IL-8和E-选择素诱导和有丝分裂抑制BMP 9。相反，激活素受体II型（ActR-II）对BMP 9介导的Smad 2激活的贡献更大。只有取消这两种II型受体显着减少Smad 1/5和Id的反应。ALK 1和BMPR-II均对HPAEC的生长抑制有贡献，而ActR-II则不参与。总之，我们的研究结果表明II型受体在平衡BMP 9信号通过ALK 1的关键作用，并强调BMPR-II在BMP 9反应的子集（白细胞介素8，E-选择素和增殖）中的重要作用。这种差异信号可能有助于遗传性出血性毛细血管扩张症和肺动脉高压的对比病理。
Mutations in transforming growth factor-beta(TGF-beta) receptor superfamily members underlie conditions characterized by vascular dysplasia. Mutations in endoglin and activin-like kinase receptor 1 (ALK1) cause hereditary hemorrhagic telangiectasia, whereas bone morphogenetic protein type II receptor (BMPR-II) mutations underlie familial pulmonary arterial hypertension. To understand the functional roles of these receptors, we examined their relative contributions to BMP signaling in human pulmonary artery endothelial cells (HPAECs). BMP9 potently and selectively induced Smad1/5 phosphorylation and Id gene expression in HPAECs. Contrary to expectations, BMP9 also stimulated Smad2 activation. Furthermore, BMP9 induced the expression of interleukin 8 and E-selectin. Using small interfering RNA, we demonstrate that the type I receptor, ALK1, is essential for these responses. However, small interfering RNA and inhibitor studies showed no involvement of ALK5 or endoglin. We further demonstrate that, of the candidate type II receptors, BMPR-II predominantly mediated IL-8 and E-selectin induction and mitogenic inhibition by BMP9. Conversely, activin receptor type II (ActR-II) contributed more to BMP9-mediated Smad2 activation. Only abolition of both type II receptors significantly reduced the Smad1/5 and Id responses. Both ALK1 and BMPR-II contributed to growth inhibition of HPAECs, whereas ActR-II was not involved. Taken together, our findings demonstrate the critical role of type II receptors in balancing BMP9 signaling via ALK1 and emphasize the essential role for BMPR-II in a subset of BMP9 responses (interleukin 8, E-selectin, and proliferation). This differential signaling may contribute to the contrasting pathologies of hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.