title: Hypoxia inducible factor-dependent regulation of angiogenesis by nitro-fatty acids.
abstract: OBJECTIVE
  Nitro-fatty acids (NO(2)-FAs) are emerging as a new class of cell signaling mediators. Because NO(2)-FAs are found in the vascular compartment and their impact on vascularization remains unknown, we aimed to investigate the role of NO(2)-FAs in angiogenesis.
  
  
  RESULTS
  The effects of nitrolinoleic acid and nitrooleic acid were evaluated on migration of endothelial cell (EC) in vitro, EC sprouting ex vivo, and angiogenesis in the chorioallantoic membrane assay in vivo. At 10 μmol/L, both NO(2)-FAs induced EC migration and the formation of sprouts and promoted angiogenesis in vivo in an NO-dependent manner. In addition, NO(2)-FAs increased intracellular NO concentration, upregulated protein expression of the hypoxia inducible factor-1α (HIF-1α) transcription factor by an NO-mediated mechanism, and induced expression of HIF-1α target genes, such as vascular endothelial growth factor, glucose transporter-1, and adrenomedullin. Compared with typical NO donors such as spermine-NONOate and deta-NONOate, NO(2)-FAs were slightly less potent inducers of EC migration and HIF-1α expression. Short hairpin RNA-mediated knockdown of HIF-1α attenuated the induction of vascular endothelial growth factor mRNA expression and EC migration stimulated by NO(2)-FAs.
  
  
  CONCLUSIONS
  Our data disclose a novel physiological role for NO(2)-FAs, indicating that these compounds induce angiogenesis in an NO-dependent mechanism via activation of HIF-1α.
authors: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors: Martina
authors: M
authors: Rudnicki
authors: Luciane A
authors: LA
authors: Faine
authors: Nathalie
authors: N
authors: Dehne
authors: Dmitry
authors: D
authors: Namgaladze
authors: Simone
authors: S
authors: Ferderbar
authors: Ricardo
authors: R
authors: Weinlich
authors: Gustavo P
authors: GP
authors: Amarante-Mendes
authors: Chao Y I
authors: CY
authors: Yan
authors: José E
authors: JE
authors: Krieger
authors: Bernhard
authors: B
authors: Brüne
authors: Dulcineia S P
authors: DS
authors: Abdalla
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008041:Linoleic Acids / Q000494:pharmacology*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology; D009574:Nitro Compounds / Q000494:pharmacology*; D009829:Oleic Acids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C501855:10-nitro-9,12-octadecadienoic acid; C521487:10-nitro-oleic acid; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008041:Linoleic Acids; D009574:Nitro Compounds; D009829:Oleic Acids; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide