miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia

Abstract

The compensatory angiogenesis that occurs after cerebral ischemia increases blood flow to the injured area and limits extension of the ischemic penumbra. In this way, it improves the local blood supply. Fostering compensatory angiogenesis is an effective treatment for ischemic cerebrovascular disease. However, angiogenesis in the adult organism is a complex, multi-step process, and the mechanisms underlying the regulation of angiogenesis are not well understood. Although Notch signaling reportedly regulates the vascularization process that occurs in ischemic tissues, little is known about the role of Notch signaling in the regulation of ischemia-induced angiogenesis after ischemic stroke. Recent research has indicated that miR-210, a hypoxia-induced microRNA, plays a crucial role in regulating the biological processes that occur in blood vessel endothelial cells under hypoxic conditions. This study was undertaken to investigate the role of miR-210 in regulating angiogenesis in response to brain ischemia injury and the role of the Notch pathway in the body's response. We found miR-210 to be significantly up-regulated in adult rat ischemic brain cortexes in which the expression of Notch1 signaling molecules was also increased. Hypoxic models of human umbilical vein endothelial cells (HUVE-12) were used to assess changes in miR-210 and Notch1 expression in endothelial cells. Results were consistent with in vivo findings. To determine the molecular mechanisms behind these phenomena, we transfected HUVE-12 cells with miR-210 recombinant lentiviral vectors. We found that miR-210 overexpression caused up-regulation of Notch1 signaling molecules and induced endothelial cells to migrate and form capillary-like structures on Matrigel. These data suggest that miR-210 is involved in the regulation of angiogenesis in response to ischemic injury to the brain. Up-regulation of miR-210 can activate the Notch signaling pathway, which may contribute to angiogenesis after cerebral ischemia.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…Furthermore, miR‐21 promotes tumour angiogenesis via upgrading the expression of VEGF 89. MiR‐210 promotes angiogenesis and the maturation of vasculature in post‐ischaemic brain tissue by enhancing the expression of Notch, VEGF and vascular endothelial growth factor receptor‐2 (VEGFR‐2) in HUVECs 90. Further research indicated that miR‐210 facilitates angiogenesis through negatively regulating the target gene, ephrin A3, which is an important member of the ephrin angiogenesis regulatory gene family 51, 91, 92.…”

Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response

“…In two independent studies, forced miR-210 expression in normoxic human umbilical vein endothelial cells (HUVECs) stimulates the formation of capillary-like structures, as well as VEGF-induced cell migration, while inhibiting miR-210 antagonizes both tubulogenesis and VEGF-mediated endothelial chemotaxis [68,144], supporting a causal role for miR-210 in promoting angiogenesis. Despite no miR-210 target having been discovered in one of these studies [144], the receptor tyrosine kinase ligand Ephrin-A3 (EFNA3) was identified as a miR-210 target for promoting the angiogenic properties of VEGF [68], consistent with the fact that the function of ephrin ligands and their receptors are important in the development of the cardiovascular system and in vascular remodeling [145].…”

Effect of Ilexonin A on the Notch signaling pathway following cerebral ischemia-reperfusion in rats

“…Simvastatin increases arteriogenesis after stroke and may work by upregulating PS1 and increasing the activity of Notch [32]. High levels of miR-210 can stimulate Notch activation and thus contribute to angiogenesis after cerebral ischemia [33]. After stroke, angiogenesis is necessary to not only restrain the ischemic zone, but also to supply a nutrient-rich environment for NSC proliferation and migration.…”