title: Annexin-1-mediated endothelial cell migration and angiogenesis are regulated by vascular endothelial growth factor (VEGF)-induced inhibition of miR-196a expression.
abstract: Endothelial cell migration induced in response to vascular endothelial growth factor (VEGF) is an essential step of angiogenesis. It depends in part on the activation of the p38/MAPKAP kinase-2/LIMK1/annexin-A1 (ANXA1) signaling axis. In the present study, we obtained evidence indicating that miR-196a specifically binds to the 3'-UTR region of ANXA1 mRNA to repress its expression. In accordance with the role of ANXA1 in cell migration and angiogenesis, the ectopic expression of miR-196a is associated with decreased cell migration in wound closure assays, and the inhibitory effect of miR-196a is rescued by overexpressing ANXA1. This finding highlights the fact that ANXA1 is a required mediator of VEGF-induced cell migration. miR-196a also reduces the formation of lamellipodia in response to VEGF suggesting that ANXA1 regulates cell migration by securing the formation of lamellipodia at the leading edge of the cell. Additionally, in line with the fact that cell migration is an essential step of angiogenesis, the ectopic expression of miR-196a impairs the formation of capillary-like structures in a tissue-engineered model of angiogenesis. Here again, the effect of miR-196a is rescued by overexpressing ANXA1. Moreover, the presence of miR-196a impairs the VEGF-induced in vivo neo-vascularization in the Matrigel Plug assay. Interestingly, VEGF reduces the expression of miR-196a, which is associated with an increased level of ANXA1. Similarly, the inhibition of miR-196a with an antagomir results in an increased level of ANXA1. We conclude that the VEGF-induced decrease of miR-196a expression may participate to the angiogenic switch by maintaining the expression of ANXA1 to levels required to enable p38-ANXA1-dependent endothelial cell migration and angiogenesis in response to VEGF.
authors: Le Centre de recherche en cancérologie de l'Université Laval and Centre de recherche du CHUQ, l'Hôtel-Dieu de Québec, 9 rue McMahon, Québec G1R 2J6, Canada.
authors: Anne-Laure
authors: AL
authors: Pin
authors: François
authors: F
authors: Houle
authors: Patrick
authors: P
authors: Fournier
authors: Maëva
authors: M
authors: Guillonneau
authors: Éric R
authors: ÉR
authors: Paquet
authors: Martin J
authors: MJ
authors: Simard
authors: Isabelle
authors: I
authors: Royal
authors: Jacques
authors: J
authors: Huot
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; D017305:Annexin A1; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A