Abstract
Endothelial to mesenchymal transition (EndMT) is an important pathological change in many diseases. Semaphorin7A (Sema7A) has been reported to regulate nerve and vessel homeostasis, but its role in EndMT remains unclear. Here we investigate the effect of Sema7A on EndMT and the underlying mechanism. Sema7A-overexpressed human umbilical vein endothelial cells (Sema7A-HUVECs) were generated and showed lower levels of endothelial cell markers and higher levels of mesenchymal cell markers indicating the occurrence of EndMT. RNA-sequencing analysis showed a total of 1168 upregulated genes and 886 downregulated genes. Among them, most of the molecules associated with EndMT were upregulated in Sema7A-HUVECs. Mechanistically, Sema7A-HUVECs showed a higher TGF-β2 expression and activated TGF-β/Smad Signaling. Importantly, Sema7A overexpression upregulated activating transcription factor 3 (ATF3) that was found to selectively bind the promotor region of TGF-β2, but not TGF-β1, promoting TGF-β2 transcription, which was further confirmed by ATF3-siRNA knockdown approach. Blocking β1 integrin, a known Sema7A receptor, alleviated the expression of ATF3, TGF-β2, and EndMT in Sema7A-overexpressed HUVECs, implying a role of β1 integrin/ATF3/TGF-β2 axis in mediating Sema7A-induced EndMT. Using Sema7A-deficient mice and the partial carotid artery ligation (PCL) model, we showed that Sema7A deletion attenuated EndMT induced by blood flow disturbance in vivo. In conclusion, Sema7A promotes TGF-β2 secretion by upregulating transcription factor ATF3 in a β1 integrin-dependent manner, and thus facilitates EndMT through TGF/Smad signaling, implying Sema7A as a potential therapeutic target for EndMT-related vascular diseases.
Highlights
During embryonic development and disease progression, endothelial cells (ECs) display a considerable plasticity of transition to other cell types, such as endothelial to mesenchymal transition (EndMT), in which the ECs lose specific endothelial markers such as CD31, VE-cadherin, EndMT-derived mesenchymal-like cells altered extracellular matrix collagen protein and matrix metalloproteinase (MMP) production, which contribute to fibrosis transition[6,7]
We showed that Sema7A promotes EndMT through TGF/Smad signaling via β1 integrin/activating transcription factor 3 (ATF3)/transforming growth factor-β2 (TGF-β2) axis and that genetic deletion of Sema7A ameliorates EndMT induced by disturb flow (d-flow), implying a potential therapeutic strategy for EndMT-related diseases by targeting Sema7A/β1 integrin and downstream signaling molecules
In the canonical signaling pathway of EndMT, TGF-β binds to the membrane receptors and phosphorylates the receptor-associated Smad proteins (Smad[2] and Smad3)
Summary
During embryonic development and disease progression, endothelial cells (ECs) display a considerable plasticity of transition to other cell types, such as endothelial to mesenchymal transition (EndMT), in which the ECs lose specific endothelial markers such as CD31, VE-cadherin, EndMT-derived mesenchymal-like cells altered extracellular matrix collagen protein and matrix metalloproteinase (MMP) production, which contribute to fibrosis transition[6,7]. Sema7A has been reported to associate with activitydependent olfactory synapse formation, pulmonary fibrosis, multiple sclerosis, T-cell-mediated inflammatory responses, and breast tumor progression[15,16,17,18,19]. Whether Sema7A is involved in the progress of EndMT is unknown, previous study reported that Sema7A promotes growth and migration of oral tongue squamous cell carcinoma by regulation epithelial–mesenchymal transition (EMT)[20]
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