Abstract
Angiogenesis, new vessel formation from pre-existing vessels, is a highly conserved event through vertebrates. However, the system for tuning angiogenesis by species-intrinsic factors is totally unknown. miR-1224 is a member of mammal-specific mirtrons, which were identified as non-canonical microRNAs. We found that the expression of miR-1224 was upregulated in capillary-like tube-forming human umbilical vein endothelial cells on Matrigel. Enforced expression of miR-1224 stimulated tube formation, whereas repression of endogenous miR-1224 inhibited formation. Enforced expression of miR-1224 enhanced VEGF signaling and repressed NOTCH signaling. The adaptor protein of clathrin-dependent endocytosis, epsin2, which has been shown to be a suppressor of angiogenesis, was a direct target of miR-1224. Knockdown of EPN2 stimulated tube formation, while overexpression of EPN2 repressed miR-1224-mediated stimulation. Our findings indicate that miR-1224 is a mammal specific modulator of angiogenesis.
Highlights
Angiogenesis is the formation of new blood vessels from preexisting vessels
We found a proangiogenic function of miR-1224 in in vitro angiogenesis using human umbilical vein endothelial cells (HUVECs) and epsin[2] as a direct target of mir-1224, providing a novel player for angiogenic modulation specific to particular mammals
By comparing the miRNA signatures of P-HUVEC (HUVECs grown on regular culture plates) and M-HUVEC (HUVECs grown on Matrigel-coated plates), we found that 56 miRNAs were upregulated more than four-fold (Table S1)
Summary
Angiogenesis is the formation of new blood vessels from preexisting vessels. During angiogenesis, VEGF and Notch signaling play key roles in angiogenic sprouting. Tip cells highly express VEGFR2 and Notch ligand Dll[4]. Vascular endothelial growth factor A (VEGF-A), a strong proangiogenic factor secreted from surrounding cells, binds to VEGFR2 on endothelial cells (ECs) of blood vessels, inducing dimerization and autophosphorylation of VEGFR23–5 to initiate signaling cascades[6,7,8]. VEGF-A induces the expression in ECs of Delta-like ligand 4 (DLL4), which suppresses sprouting by activating NOTCH on adjacent cells as its ligand[9, 10], to form the stalk cells via reducing VEGFR2 expression. We found a proangiogenic function of miR-1224 in in vitro angiogenesis using human umbilical vein endothelial cells (HUVECs) and epsin[2] as a direct target of mir-1224, providing a novel player for angiogenic modulation specific to particular mammals
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