Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

Abstract

Background: MicroRNAs mediate angiogenesis in both physiological and pathological conditions, but underlying molecular mechanisms are largely unexplored. Results: Endothelial miR-15a negatively regulates angiogenesis in vivo and in vitro by suppression of FGF2 and VEGF. Conclusion: MiR-15a inhibits endothelial autonomous angiogenesis. Significance: MiR-15a is a negative regulator of angiogenesis and a potential target for the restorative therapy of ischemic diseases.

Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 Increases Neovascularization and Blood Flow Recovery After Ischemia

“…In the initial RTP, we included 127 genes that are known to be involved in neovascularization from both literature and our own studies (Online Table IA). As anticipated, we observed enrichment of putative binding sites for several microRNAs that were previously reported to influence postischemic neovascularization, including miR-17/92a 9 (29 and 21 putative target genes, respectively), miR-106b/93/25 8,14 (29,29, and 21 putative target genes, respectively), the miR-15a family 10,11,25 (26 putative target genes), miR-503 13 (11 putative target genes), and miR-100 7 (2 putative target genes) but not, for example, miR-126. 6 However, more outspoken was the enrichment of putative binding sites for 27 microRNAs from the 14q32 microRNA gene cluster, including miR-329, miR-494, and miR-495 (20, 31, and 44 putative target genes, respectively).…”

“…The authors described an absolute increase in perfusion of 10% to 15% at day 7 after double ligation of the femoral artery in C57BL/6 mice. Finally in 2012, Yin et al 10 took an opposite approach and demonstrated that overexpression of miR-15a attenuates postischemic blood flow recovery, resulting in an absolute decrease of perfusion of 10% at day 7 and 25% at day 14 after excision of the femoral artery, compared with control animals.…”

“…[6][7][8][9][10][11][12][13][14] In the present study, we exploited the master switch character of microRNAs to identify microRNAs that play a regulatory role in neovascularization as a whole, including both angiogenesis and arteriogenesis. We performed a reverse target prediction (RTP) analysis on a set of ≈200 genes involved in all facets of angiogenesis and arteriogenesis, aiming to identify microRNAs that can target multiple neovascularization genes.…”

p53-Induced miR-15a/16-1 and AP4 Form a Double-Negative Feedback Loop to Regulate Epithelial–Mesenchymal Transition and Metastasis in Colorectal Cancer

“…Furthermore, miR-15a/16-1 inhibits the growth of the cancer stem cell population in breast cancer (44). In addition, miR15a/16-1 suppresses angiogenesis by targeting VEGF (45,46). Interestingly, the protooncogene c-MYC, which directly regulates AP4, was shown to repress the transcription of DLEU2, and therefore decrease miR-15a/16-1 expression through direct binding in the vicinity of the two transcription start sites, presumably via recruiting histone deacetylase 3 (47).…”

Exosomes

“…In addition to being conjugated to argonaute-2, the miRNAs were found within exosomes, 70 suggesting their potential as markers of critical limb ischemia. Because miR-15a seems to inhibit angiogenesis, 71 it will be interesting to determine whether exosomes actually contribute to ischemic injury in this case. In other situations, the injection of proangiogenic exosomes can be beneficial.…”