Signaling by ALK5 mediates TGF-β-induced ET-1 expression in endothelial cells:: a role for migration and proliferation
Signaling by ALK5 mediates TGF-β-induced ET-1 expression in endothelial cells:: a role for migration and proliferation
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DOI：
10.1242/jcs.03419
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发表时间：
2007-04-01
影响因子：
4
通讯作者：
Rodriguez-Pascual, Fernando
中科院分区：
文献类型：
--
作者：
Castanares, Cristina;Redondo-Horcajo, Mariano;Rodriguez-Pascual, Fernando
内皮素-1（ET-1）是一种有效的内皮源性21个氨基酸的血管收缩肽，其表达受细胞因子转化生长因子-β（TGF-β）的有效调节。大多数细胞类型含有TGF-β I型受体形式，称为激活素受体样激酶5（ALK 5）。然而，内皮细胞共表达另一种名为ALK 1的I型受体。这些形式不构成具有相同功能的冗余受体，但它们激活不同的Smad介导的表达程序，导致特定的内皮表型。我们的研究的目的是表征TGF-β诱导的途径导致内皮细胞中ET-1的表达和TGF-β介导的ET-1的增强对内皮细胞迁移和增殖能力的调节的贡献。我们的实验表明，TGF-β诱导ET-1的表达优先通过ALK 5/Smad3途径。特异性ALK 5抑制完全阻断了TGF-β的抗血管生成作用。ET受体的拮抗作用部分逆转了TGF-β的作用，表明该细胞因子的抗迁移和抗增殖作用的显著部分是由ET-1以自分泌方式作用于内皮细胞介导的。
Endothelin-1 (ET-1) is a potent endothelial-derived 21 amino-acid vasoconstrictor peptide and its expression is potently regulated by the cytokine transforming growth factor-beta (TGF-beta). Most cell types contain a TGF-beta type I receptor form known as activin receptor-like kinase 5 (ALK5). However, endothelial cells coexpress an additional type I receptor named ALK1. These forms do not constitute redundant receptors with the same function, but they activate different Smad- mediated expression programmes leading to specific endothelial phenotypes. The aim of our study was to characterize the TGF-beta-induced pathway leading to ET-1 expression in endothelial cells and the contribution of the TGF-beta-mediated enhancement of ET-1 to the regulation of the endothelial cell migration and proliferation capacity. Our experiments indicate that TGF-beta induces ET-1 expression preferentially through the ALK5/Smad3 pathway. Specific ALK5 inhibition totally blocked the anti-angiogenic effect of TGF-beta. Antagonism of ET receptors partially reverted the effect of TGF-beta, indicating that a significant portion of the anti-migratory and anti-proliferative actions of this cytokine is mediated by ET-1 acting in an autocrine manner on endothelial cells.