MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3*

By P. Fasanaro, Y. D'Alessandra, V. Di Stefano, R. Melchionna, Sveva Romani, G. Pompilio, M. Capogrossi, F. Martelli. Journal of Biological Chemistry, 2008

917 citations recorded by the source corpus.

MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3c1e0b450ef33585048b9d4c597e803e8ae702fc

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Citations in the corpus

Hypoxia-induced angiogenesis: good and evil. (2011, background): “In the endothelium, miR-210 is an HIF-1α target, and hypoxic miR-210 induction promotes endothelial tube formation and EC migration by downregulating Ephrin-A3.(87) In the endothelium, HIF-1α promotes expression of VEGF and its receptor VEGF-R2, thereby regulating an autocrine VEGF signaling loop th”
MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2 (2009, neutral): “Some, but not all, of these miRNA have been identified in other transformed (Kulshreshtha et al., 2007) or primary endothelial cells (Fasanaro et al., 2008) exposed to hypoxia.”
Circulating microRNAs are new and sensitive biomarkers of myocardial infarction (2010, background): “Many miRNAs exhibit a tissue-specific distribution and they appear to play a key role in cell function both under physiological and pathological conditions; indeed, marked changes in the tissue level of some miRNAs have been found in myocardial infarction (MI), 5 cardiac hypertrophy,(6) heart failur”
MicroRNAs in development and disease. (2011, background): “Similarly, miR-210, which is induced by hypoxia (72, 171), was sufficient for inducing tubulogenesis in HUVEC cells (171).”
Role of microRNAs in vascular diseases, inflammation, and angiogenesis. (2008, background): “MiR-210 overexpression enhanced the formation of capillary-like structures and VEGF-driven migration of normoxic endothelial cells, whereas inhibition of miR-210 decreased tube formation and migration.(38) The modulation of endothelial cell responses to hypoxia is mediated via the regulation of the ”
Neutral Sphingomyelinase 2 (nSMase2)-dependent Exosomal Transfer of Angiogenic MicroRNAs Regulate Cancer Cell Metastasis (2013, methodology): “Then, we employed this co-culture system to study the effects of exosomes isolated from parental 4T1 cells on the expression of the established miR-210 target gene, ephrin-A3 (26).”
Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs (2012, background): “KLF2 reduced the expression level of miR-210, which is involved in angiogenesis and the hypoxia response of endothelial cell”
Eph receptors and ephrins in cancer: bidirectional signaling and beyond (2010, background): “Expression of EPHA2–ephrin-A1 and EPHB4–ephrin-B2 in tumour blood vessels has been most extensively characterized, but other Eph receptors and ephrins are also present in the tumour vasculatur”
Hypoxia inducible mir-210 regulates normoxic gene expression involved in tumor initiation (2009, positive): “Cells may utilize mir-210 to fine-tune EFNA3 expression, as EFNA3 has recently also been reported as a mir-210 target by other groups (Fasanaro et al., 2008; Pulkkinen et al., 2008).”
Hypoxic enhancement of exosome release by breast cancer cells (2012, background): “This could play a role in promoting tumour progression in response to hypoxia, as miR-210 can promote endothelial cell tubulogenesis [52], as well as repressing DNA repair pathways [53].”