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

FASEB J. 2020 May;34(5):7178-7191. doi: 10.1096/fj.202000201R. Epub 2020 Apr 10.

Abstract

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.

Keywords: endothelial-mesenchymal transition (endMT); ischemic stroke; let-7; transforming growth factor-β receptor type 1 (TGF-βR1); vascular fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • MicroRNAs
  • mirnlet7 microRNA, mouse
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, mouse