Clinical and Experimental Therapeutics, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, United States.
Clinical and Experimental Therapeutics, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, United States; Department of Medicine and Vascular Biology Center, Augusta University, Augusta, GA, United States.
Gene. 2021 Feb 5;768:145293. doi: 10.1016/j.gene.2020.145293. Epub 2020 Nov 4.
Endothelial-to-mesenchymal transition (EndMT) indispensable in embryogenesis also occurs in several human pathologies. Although transforming growth factor-β (TGFβ) has been demonstrated to induce EndMT, the type-I receptors (ALK-1 and ALK-5) responsible for TGFβ-induced EndMT is unclear. In the current study, we investigated the role of the Akt1 pathway in ALK1 and ALK5 expression regulation in response to TGFβ1 and TGFβ2 in human microvascular endothelial cells (HMECs). Whereas treatment with TGFβ1 and TGFβ2 or Akt1 gene silencing promoted EndMT accompanied by increased ALK5 expression and reduced ALK1 expression accompanied by increased expression of N-cadherin and reduced expression of eNOS in HMECs, treatment with ALK-5 inhibitor (SB431542) blunted these effects. Importantly, the inhibitor of β-catenin (ICG-001) suppressed TGFβ1- and TGFβ2-induced ALK5 expression in both normal and Akt1 deficient HMECs indicating the integral role of Akt1-β-catenin pathway in the regulation of ALK5 expression promoting EndMT.
内皮-间质转化（EndMT）在胚胎发生中不可或缺，也发生在几种人类病理中。虽然转化生长因子-β（TGFβ）已被证明可诱导EndMT，但负责 TGFβ 诱导的 EndMT 的 I 型受体（ALK-1 和 ALK-5）尚不清楚。在本研究中，我们研究了 Akt1 通路在人微血管内皮细胞（HMECs）中对 TGFβ1 和 TGFβ2 反应中 ALK1 和 ALK5 表达调节中的作用。虽然 TGFβ1 和 TGFβ2 或 Akt1 基因沉默的处理促进了 EndMT，伴随着 ALK5 表达的增加和 ALK1 表达的减少，伴随着 N-钙粘蛋白的增加表达和 eNOS 的减少表达，ALK-5 抑制剂（SB431542）的处理减弱了这些效应。重要的是，β-连环蛋白抑制剂（ICG-001）抑制了正常和 Akt1 缺陷 HMECs 中 TGFβ1 和 TGFβ2 诱导的 ALK5 表达，表明 Akt1-β-连环蛋白通路在调节 ALK5 表达促进 EndMT 中具有整体作用。
