Department of Molecular Cell Biology, and Centre for Biomedical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.
Histol Histopathol. 2011 Sep;26(9):1219-30. doi: 10.14670/HH-26.1219.
Genetic studies in mice and humans have revealed a pivotal function for transforming growth factor-beta (TGF-β) in vascular development and maintenance of vascular homeostasis. Mice deficient for various TGF-β signaling components develop an embryonic lethality due to vascular defects. In patients, mutations in TGF-β receptors have been linked to vascular dysplasia like Hereditary Hemorrhagic Telangiectasia (HHT) and pulmonary arterial hypertension (PAH). Besides indirect effects by regulating the expression of angiogenic regulators, TGF-β also has potent direct effects on endothelial cell growth and migration, and we have proposed that TGF-β regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways, activin receptor-like kinase (ALK)1 and ALK5. TGF-β is also critical for the differentiation of mural precursors into pericytes and smooth muscle cells. Furthermore, defective paracrine TGF-β signaling between endothelial and neighboring mural cells may be responsible for a leaky vessel phenotype that is characteristic of HHT. In this review, we discuss our current understanding of the TGF-β signaling pathway and its regulation of endothelial and vascular smooth muscle cell function.
遗传研究在小鼠和人类中揭示了转化生长因子-β（TGF-β）在血管发育和维持血管稳态中的关键作用。缺乏各种 TGF-β信号成分的小鼠由于血管缺陷而导致胚胎致死。在患者中，TGF-β受体的突变与血管发育不良有关，如遗传性出血性毛细血管扩张症（HHT）和肺动脉高压（PAH）。除了通过调节血管生成调节剂的表达产生间接作用外，TGF-β对内皮细胞的生长和迁移也具有很强的直接作用，我们提出 TGF-β通过两种相反的 I 型受体/Smad 途径，激活素受体样激酶（ALK）1 和 ALK5 来调节内皮细胞的激活状态。TGF-β对于壁细胞前体分化为周细胞和平滑肌细胞也很重要。此外，内皮细胞和相邻壁细胞之间旁分泌 TGF-β信号的缺陷可能是导致 HHT 特征性的血管渗漏表型的原因。在这篇综述中，我们讨论了我们对 TGF-β信号通路及其对内皮细胞和血管平滑肌细胞功能的调节的理解。
