Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis
Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis
复制标题
DOI：
10.1073/pnas.97.6.2626
复制
发表时间：
2000-03-14
影响因子：
11.1
通讯作者：
Li, E
中科院分区：
文献类型：
--
作者：
Oh, SP;Seki, T;Li, E
激活素受体样激酶1（ALK 1）是转化生长因子β（TGF-β）家族蛋白的I型受体。ALK 1在血管中的表达和人类II型遗传性出血性毛细血管扩张症患者中ALK 1基因的突变表明ALK 1可能在血管发育过程中发挥重要作用，为了定义ALK 1在发育过程中的功能，我们通过基因靶向灭活了小鼠中的ALK 1基因。ALK 1纯合子胚胎在妊娠中期死亡，表现出严重的血管异常，其特征是毛细血管丛过度融合成海绵状血管和大血管过度扩张。这些血管缺陷与血管生成因子和蛋白酶的表达增强有关，其特征在于血管平滑肌细胞的分化和募集不足。ALK 1缺陷小鼠的血管缺陷使人联想到缺乏TGF-β 1、TGF-β II型受体（T β R-II）或内皮糖蛋白的小鼠，这表明ALK 1可能介导内皮细胞中的TGF-β 1信号。与这一假设相一致，我们证明了内皮细胞中的ALK 1与TGF-β 1和T β R-II结合。此外，ALK 1信号传导途径可抑制由已知的TGF-β 1 I型受体ALK 5介导的TGF-β 1依赖性转录激活。综上所述，我们的研究结果表明，在血管生成过程中，内皮细胞中ALK 1和ALK 5信号通路之间的平衡在确定血管内皮特性方面起着至关重要的作用。
The activin receptor-like kinase 1 (ALK1) is a type I receptor for transforming growth factor-beta (TGF-beta) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development, To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-beta 1, TGF-beta type II receptor (T beta R-II), or endoglin, suggesting that ALK1 may mediate TGF-beta 1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-beta 1 and T beta R-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-beta 1-dependent transcriptional activation mediated by the known TGF-beta 1 type I receptor, ALK5. Taken together, our results suggest that the balance between the ALK1 and ALK5 signaling pathways in endothelial cells plays a crucial role in determining vascular endothelial properties during angiogenesis.