Ischemia-reperfusion injury of brain induces endothelial-mesenchymal transition and vascular fibrosis via activating let-7i/TGF-βR1 double-negative feedback loop

• Published in: The FASEB journal Vol. 34; no. 5; p. 7178
• Main Authors: Chen, Danqi, Li, Ling, Wang, Ying, Xu, Ruoting, Peng, Shunli, Zhou, Liang, Deng, Zhen
• Format: Journal Article
• Language: English
• Published: United States 01.05.2020
• Subjects: Animals; Blood-Brain Barrier - pathology; Blood-Brain Barrier - physiopathology; Cell Transdifferentiation; Cerebrovascular Trauma - pathology; Cerebrovascular Trauma - physiopathology; Disease Models, Animal; Endothelium - pathology; Endothelium - physiopathology; Feedback, Physiological; Fibrosis; Gene Knockdown Techniques; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Male; Mesoderm - pathology; Mesoderm - physiopathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs - genetics; MicroRNAs - physiology; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I - deficiency; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - physiology; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; endothelial-mesenchymal transition (endMT); let-7; transforming growth factor-β receptor type 1 (TGF-βR1); ischemic stroke; vascular fibrosis
• ISSN: 1530-6860
• DOI: 10.1096/fj.202000201R

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.