MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells

Abstract

Objective: In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro-and anti-angiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results: We show that in response to tissue injury, miR-615-5p is rapidly induced and serves as an anti-angiogenic miRNA by targeting endothelial cell (EC) VEGF-AKT/ eNOS signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes. Ectopic expression of miR-615-5p markedly inhibited EC proliferation, migration, network tube formation in matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using

Extracellular Vesicle-Derived microRNAs of Human Wharton’s Jelly Mesenchymal Stromal Cells May Activate Endogenous VEGF-A to Promote Angiogenesis

“…MSC-derived EVs have a documented capacity to actively modulate blood vessel formation [ 9 , 10 , 11 ], as well as to promote angiogenesis in animal models of myocardial infarction [ 12 , 13 , 14 ] and wound healing [ 15 ], so that their administration is an emerging approach to treat ischemic diseases. The regulation of angiogenesis-related disorders by EVs has been attributed especially to the transfer of microRNAs (miRNAs) [ 16 , 17 , 18 , 19 ] that modulate the expression of angiogenic genes, such as vascular endothelial growth factor ( VEGF ), matrix metalloproteinases ( MMPs), platelet-derived growth factor ( PDGF ), fibroblast growth factor ( FGF ) and epidermal growth factor ( EGF ) [ 20 ].…”

miRNA/Target Gene Profile of Endothelial Cells Treated with Human Triglyceride‐Rich Lipoproteins Obtained after a High‐Fat Meal with Extra‐Virgin Olive Oil or Sunflower Oil

“…A group of upregulated miRNAs with SO-derived TRLs could be involved in the development of insulin resistance, such as miR-615-5p, miR-495, and miR-494-3p. [28][29][30] Also, there are a group of DE-miRNAs included in other pathways related to endothelial dysfunction. Some of these miRNAs were also related to atherosclerosis, but there was another group of exclusive DE-miRNAs.…”

miR-615 Fine-Tunes Growth and Development and Has a Role in Cancer and in Neural Repair

“…In patients with diseases associated with vascular dysfunction, such as acute coronary syndrome (ACS), diabetes mellitus (DM) or systemic arterial hypertension (SAH), miR-615-5p is overexpressed in peripheral blood [29,30]. In experimental models of vascular dysfunction and tissue damage, including wounds in diabetic mice and human skin organoids, miR-615-5p significantly inhibits VEGF, AKT and eNOS signaling, which could suppress the angiogenic signals and restorative processes such as granulation tissue formation and wound healing.…”

“…In experimental models of vascular dysfunction and tissue damage, including wounds in diabetic mice and human skin organoids, miR-615-5p significantly inhibits VEGF, AKT and eNOS signaling, which could suppress the angiogenic signals and restorative processes such as granulation tissue formation and wound healing. This effect is achieved by directly targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras association domain family member 2), as an accumulative effect [29]. The IGF-axis is also modulated by miR-615-5p in NK cells of hepatocellular carcinoma (HCC) patients, in which upregulation of miR-615-5p directly represses IGFR1 signaling and reduces the cytotoxic markers NKG2D, TNF-a and perforins.…”

“…Similarly to its 3p counterpart, miR-615-5p suppresses the transcription of numerous oncogenes through specific binding to sequences in the 3'-UTR region, such as AKT [9,29,56,59,60], CCND2 [62] and IGFR1/IGF2-axis [27,31,[56][57][58]64]. In pancreatic adenocarcinoma (PAC), miR-615-5p has reduced expression in malignant cells compared to adjacent normal pancreatic acinar cells.…”