Ischemia‐reperfusion injury of brain induces endothelial‐mesenchymal transition and vascular fibrosis via activating let‐7i/TGF‐βR1 double‐negative feedback loop
| Autor: | Ying Wang, Shunli Peng, Zhen Deng, Ruoting Xu, Danqi Chen, Liang Zhou, Ling Li |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Receptor Transforming Growth Factor-beta Type I Ischemia Mice Transgenic Inflammation Biochemistry Mesoderm Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Cerebrovascular Trauma Endothelium Molecular Biology Feedback Physiological Gene knockdown business.industry Mesenchymal stem cell Antagonist Infarction Middle Cerebral Artery medicine.disease Fibrosis Rats Mice Inbred C57BL Disease Models Animal MicroRNAs 030104 developmental biology Blood-Brain Barrier Gene Knockdown Techniques Reperfusion Injury Cell Transdifferentiation Cancer research Phosphorylation medicine.symptom business Reperfusion injury 030217 neurology & neurosurgery Biotechnology Transforming growth factor |
| Zdroj: | The FASEB Journal. 34:7178-7191 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.202000201r |
| Popis: | Let-7i modulates the physical function and inflammation in endothelial cells (ECs). However, whether the let-7i of ECs involves in brain vasculature and ischemic stroke is unknown. Using inducible Cadherin5-Cre lineage-tracking mice, a loxp-RNA-sponge conditional knockdown of let-7 in ECs- induced increase of transforming growth factor-β receptor type 1 (TGF-βR1), endothelial-mesenchymal transition (endMT), vascular fibrosis, and opening of the brain-blood barrier (BBB). By this lineage-tracking mice, we found that ECs underwent endMT after transient middle cerebral artery occlusion (MCAO). Through specifically overexpressed let-7i in ECs, we found that it reduced TGF-βR1, endMT, and vascular fibrosis. Furthermore, this overexpression reduced the infarct volume and leakage of the BBB, and improved the neurological function. Further, the expression of let-7i decreased after MCAO, but was reversed by antagonist of TGF-βR1 or inhibition of Mek phosphorylation. And the inhibition of Mek attenuated the vascular fibrosis after MCAO. In summary, we concluded that ischemic stroke activates a let-7i/TGF-βR1 double-negative feedback loop, thereby inducing endMT and vascular fibrosis. These results suggest that endMT is a potential target for the treatment of cerebral vascular fibrosis. |
| Databáze: | OpenAIRE |
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