title: PACAP and VIP Inhibit HIF-1α-Mediated VEGF Expression in a Model of Diabetic Macular Edema.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) exert a protective role against retinal injuries, including diabetic macular edema (DME). The macular damage is induced by hyperglycemia, which damages vessels supplying blood to the retina and induces hypoxia. The microenvironmental changes stimulate the expression of hypoxia-inducible factors (HIFs), which promote the choroidal endothelial cell transmigration across the retinal pigmented epithelium (RPE) into neurosensory retina, where they proliferate into new vessels under stimulation of the vascular endothelial growth factor (VEGF). In the present study, we have investigated whether PACAP and VIP prevent retinal damage by modulating the expression of HIFs, VEGF, and its receptors. In accord to our hypothesis, we have shown that both peptides are able to significantly reduce HIF-1α and increase HIF-3α expression in ARPE-19 cells exposed to hyperglycemic/hypoxic insult. This effect is also related to a reduction of VEGF and its receptors expression. Moreover, both peptides also reduce the activation of p38 mitogen-activated protein kinase (MAPK), a pro-apoptotic signaling pathway, which is activated by VEGFR-1 and 2 receptors. In conclusion, our study has further elucidated the protective role performed by PACAP and VIP, against the harmful combined effect of hyperglycemia/hypoxia characterizing the DME microenvironment. J. Cell. Physiol. 232: 1209-1215, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Maugeri
authors.affiliation: Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.|San Raffaele Telematic University of Rome, Rome, Italy.
authors.forename: Agata Grazia
authors.initials: AG
authors.lastname: D'Amico
authors.affiliation: Section of Animal Biology, Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Saccone
authors.affiliation: Section of Animal Biology, Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Federico
authors.affiliation: Institute of Neurological Sciences, Italian National Research Council, Catania, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
authors.affiliation: Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Velia
authors.initials: V
authors.lastname: D'Agata
mesh_terms: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008269:Macular Edema / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D012097:Repressor Proteins; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012097:Repressor Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D014660:Vasoactive Intestinal Peptide; D048051:p38 Mitogen-Activated Protein Kinases; C116973:HIF3A protein, human