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Isoform-Specific Effects of Transforming Growth Factor-β on Endothelial to Mesenchymal Transition

机译：转化生长因子-β对内皮细胞向间充质转化的同工型特异性效应

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Endothelial to mesenchymal transition (EndMT) was first reported in the embryogenesis. Recent studies show that EndMT also occurs in the disease progression of atherosclerosis, cardiac and pulmonary fibrosis, pulmonary hypertension, diabetic nephropathy, and cancer. Although transforming growth factor-β (TGFβ) is crucial for EndMT, it is not clear which isoform elicits a predominant effect. The current study aims to directly compare the dose-dependent effects of TGFβ1, TGFβ2, and TGFβ3 on EndMT and characterize the underlying mechanisms. In our results, all the three TGFβ isoforms induced EndMT in human microvascular endothelial cells (HMECs) after 72 hours, as evidenced by the increased expression of mesenchymal markers N-cadherin and alpha-smooth muscle actin (αSMA) as well as the decreased expression of endothelial nitric oxide synthase (eNOS). Interestingly, the effect of TGFβ2 was the most pronounced. At 1 ng/ml, only TGFβ2 treatment resulted in significantly increased phosphorylation (activation) of Smad2/3 and p38-MAPK and increased expression of mesenchymal transcription factors Snail and FoxC2. Intriguingly, we observed that treatment with 1 ng/ml TGFβ1 and TGFβ3, but not TGFβ2 resulted in increased expression of TGFβ2 thus indicating that EndMT with TGFβ1 and TGFβ3 treatments was due to the secondary effects through TGFβ2 secretion. Furthermore, silencing TGFβ2 using siRNA blunted the expression of EndMT markers in TGFβ1 and TGFβ3 treated cells. Together, our results indicate that TGFβ2 is the most potent inducer of EndMT and that TGFβ1- and TGFβ3-induced EndMT necessitates a paracrine loop involving TGFβ2.
机译：内皮细胞向间质转化（EndMT）最早在胚胎发生中报道。最近的研究表明，EndMT还发生在动脉粥样硬化，心脏和肺纤维化，肺动脉高压，糖尿病肾病和癌症的疾病进展中。尽管转化生长因子-β（TGFβ）对于EndMT至关重要，但尚不清楚哪种同种型引起主要作用。本研究旨在直接比较TGFβ1，TGFβ2和TGFβ3对EndMT的剂量依赖性作用，并表征其潜在机制。在我们的结果中，所有三种TGFβ同工型在72小时后均诱导了人微血管内皮细胞（HMEC）的EndMT，这由间充质标记物N-钙黏着蛋白和α-平滑肌肌动蛋白（αSMA）的表达增加以及表达的减少证明了这一点。一氧化氮合酶（eNOS）的表达。有趣的是，TGFβ2的作用最为明显。在1 ng / ml时，仅TGFβ2处理导致Smad2 / 3和p38-MAPK的磷酸化（激活）显着增加，并且间充质转录因子Snail和FoxC2的表达增加。有趣的是，我们观察到用1 ng / mlTGFβ1和TGFβ3进行处理，而不用TGFβ2进行处理会导致TGFβ2的表达增加，因此表明用TGFβ1和TGFβ3处理的EndMT是由于TGFβ2分泌引起的次级作用。此外，使用siRNA沉默TGFβ2使TGFβ1和TGFβ3处理的细胞中EndMT标记的表达减弱。总之，我们的结果表明TGFβ2是EndMT的最强诱导剂，而TGFβ1和TGFβ3诱导的EndMT需要涉及TGFβ2的旁分泌环。

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