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Vascular Endothelial Growth Factor Signaling in Hypoxia and Inflammation

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Abstract

Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by re-programming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions.

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References

  • Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1(3):219–227

    CAS  PubMed  Google Scholar 

  • Ando H et al (2013) A hypoxia-inducible factor (HIF)-3alpha splicing variant, HIF-3alpha4 impairs angiogenesis in hypervascular malignant meningiomas with epigenetically silenced HIF-3alpha4. Biochem Biophys Res Commun 433(1):139–144

    CAS  PubMed  Google Scholar 

  • Andreoli CM, Miller JW (2007) Anti-vascular endothelial growth factor therapy for ocular neovascular disease. Curr Opin Ophthalmol 18(6):502–508

    PubMed  Google Scholar 

  • Antoine M et al (2005) Upregulation of pleiotrophin expression in rat hepatic stellate cells by PDGF and hypoxia: implications for its role in experimental biliary liver fibrogenesis. Biochem Biophys Res Commun 337(4):1153–1164

    CAS  PubMed  Google Scholar 

  • Arnaud C, Poulain L, Levy P, Dematteis M (2011) Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice. Atherosclerosis 219(2):425–431

    CAS  PubMed  Google Scholar 

  • Barreiro O et al (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157(7):1233–1245

    CAS  PubMed Central  PubMed  Google Scholar 

  • Battaglia F et al (2008) Hypoxia transcriptionally induces macrophage-inflammatory protein-3alpha/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-kappaB. J Leukoc Biol 83(3):648–662

    CAS  PubMed  Google Scholar 

  • Bella J, Kolatkar PR, Marlor CW, Greve JM, Rossmann MG (1998) The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand. Proc Natl Acad Sci U S A 95(8):4140–4145

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bellot G et al (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29(10):2570–2581

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bosco MC et al (2004) Hypoxia selectively inhibits monocyte chemoattractant protein-1 production by macrophages. J Immunol 172(3):1681–1690

    CAS  PubMed  Google Scholar 

  • Bosco MC et al (2006) Hypoxia modifies the transcriptome of primary human monocytes: modulation of novel immune-related genes and identification of CC-chemokine ligand 20 as a new hypoxia-inducible gene. J Immunol 177(3):1941–1955

    CAS  PubMed  Google Scholar 

  • Bosco MC et al (2008) Monocytes and dendritic cells in a hypoxic environment: Spotlights on chemotaxis and migration. Immunobiology 213(9–10):733–749

    CAS  PubMed  Google Scholar 

  • Braunwald E (2013) Cardiovascular science: opportunities for translating research into improved care. J Clin Invest 123(1):6–10

    CAS  PubMed Central  PubMed  Google Scholar 

  • Carmeliet P et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573):435–439

    CAS  PubMed  Google Scholar 

  • Carmeliet P et al (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7(5):575–583

    CAS  PubMed  Google Scholar 

  • Carriere V et al (2007) IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A 104(1):282–287

    CAS  PubMed Central  PubMed  Google Scholar 

  • Carroll VA, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 66(12):6264–6270

    CAS  PubMed  Google Scholar 

  • Chakravorty SJ, Craig A (2005) The role of ICAM-1 in plasmodium falciparum cytoadherence. Eur J Cell Biol 84(1):15–27

    CAS  PubMed  Google Scholar 

  • Chan SY et al (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10(4):273–284

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chang JH et al (2012) Corneal neovascularization: an anti-VEGF therapy review. Surv Ophthalmol 57(5):415–429

    PubMed Central  PubMed  Google Scholar 

  • Chen WY, Chang MS (2009) IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. J Immunol 182(8):5003–5012

    CAS  PubMed  Google Scholar 

  • Chen M, Geng JG (2006) P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arc Immunol Ther Exp 54(2):75–84

    CAS  Google Scholar 

  • Chen R et al (2012) The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling. J Biol Chem 287(36):30800–30811

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chistiakov DA, Sobenin IA, Orekhov AN (2012) Strategies to deliver microRNAs as potential therapeutics in the treatment of cardiovascular pathology. Drug Deliv 19(8):392–405

    CAS  PubMed  Google Scholar 

  • Cicchillitti L et al (2012) Hypoxia-inducible factor 1-alpha induces miR-210 in normoxic differentiating myoblasts. J Biol Chem 287(53):44761–44771

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ciulla TA, Rosenfeld PJ (2009) Anti-vascular endothelial growth factor therapy for neovascular ocular diseases other than age-related macular degeneration. Curr Opin Ophthalmol 20(3):166–174

    PubMed  Google Scholar 

  • Cleator JH, Zhu WQ, Vaughan DE, Hamm HE (2006) Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood 107(7):2736–2744

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cohen T et al (1995) VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells. J Biol Chem 270(19):11322–11326

    CAS  PubMed  Google Scholar 

  • Colgan SP, Taylor CT (2010) Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7(5):281–287

    PubMed  Google Scholar 

  • Dhondt J et al (2011) Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. FASEB J Off Publ Fed Am Soc Exp Biol 25(5):1461–1473

    CAS  Google Scholar 

  • Dias S et al (2000) Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 106(4):511–521

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dioum EM et al (2009) Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324(5932):1289–1293

    CAS  PubMed  Google Scholar 

  • Dumont DJ et al (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282(5390):946–949

    CAS  PubMed  Google Scholar 

  • Egger M et al (2007) Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1alpha- and basic FGF-dependent pathway in muscle cells. FASEB J 21(11):2906–2917

    CAS  PubMed  Google Scholar 

  • Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364(7):656–665

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ema M et al (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 94(9):4273–4278

    CAS  PubMed Central  PubMed  Google Scholar 

  • Falanga V et al (1991) Hypoxia upregulates the synthesis of TGF-beta 1 by human dermal fibroblasts. J Invest Dermatol 97(4):634–637

    CAS  PubMed  Google Scholar 

  • Favaro E et al (2010) MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PloS ONE 5(4):e10345

    PubMed Central  PubMed  Google Scholar 

  • Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611

    CAS  PubMed  Google Scholar 

  • Ferrara N (2010) Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell 21(5):687–690

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ferrara N et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573):439–442

    CAS  PubMed  Google Scholar 

  • Florczyk U et al (2011) Opposite effects of HIF-1alpha and HIF-2alpha on the regulation of IL-8 expression in endothelial cells. Free Radic Biol Med 51(10):1882–1892

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376(6535):66–70

    CAS  PubMed  Google Scholar 

  • Frangogiannis NG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovasc Res 53(1):31–47

    CAS  PubMed  Google Scholar 

  • Fu H, Luo F, Yang L, Wu W, Liu X (2010) Hypoxia stimulates the expression of macrophage migration inhibitory factor in human vascular smooth muscle cells via HIF-1alpha dependent pathway. BMC Cell Biol 11:66

    PubMed Central  PubMed  Google Scholar 

  • Fukumura D et al (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94(6):715–725

    CAS  PubMed  Google Scholar 

  • Gameiro PA et al (2013) In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17(3):372–385

    CAS  PubMed  Google Scholar 

  • Ganat Y, Soni S, Chacon M, Schwartz ML, Vaccarino FM (2002) Chronic hypoxia up-regulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor-responsive radial glial cells in the sub-ependymal zone. Neuroscience 112(4):977–991

    CAS  PubMed  Google Scholar 

  • Gerber HP, Ferrara N (2003) The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med (Berl Germany) 81(1):20–31

    CAS  Google Scholar 

  • Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N (2000) Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res 60(22):6253–6258

    CAS  PubMed  Google Scholar 

  • Ghezzi P et al (1991) Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokine 3(3):189–194

    CAS  PubMed  Google Scholar 

  • Ghosh G et al (2010) Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest 120(11):4141–4154

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gonsalves CS, Kalra VK (2010) Hypoxia-mediated expression of 5-lipoxygenase-activating protein involves HIF-1alpha and NF-kappaB and microRNAs 135a and 199a-5p. J Immunol 184(7):3878–3888

    CAS  PubMed  Google Scholar 

  • Greenberg DA, Jin K (2013) Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci 70(10):1753–1761

    CAS  PubMed  Google Scholar 

  • Gupta R, Tongers J, Losordo DW (2009) Human studies of angiogenic gene therapy. Circ Res 105(8):724–736

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hagberg CE et al (2010) Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464(7290):917–921

    CAS  PubMed  Google Scholar 

  • Hagberg CE et al (2012) Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490(7420):426–430

    CAS  PubMed  Google Scholar 

  • Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U (2013) Endothelial fatty acid transport: role of vascular endothelial growth factor B. Physiology 28(2):125–134

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hagerling R et al (2013) A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 32(5):629–644

    PubMed Central  PubMed  Google Scholar 

  • Haiko P et al (2008) Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol 28(15):4843–4850

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hara S et al (2006) Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Oral Oncol 42(6):593–598

    CAS  PubMed  Google Scholar 

  • Hedman M et al (2003) Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 107(21):2677–2683

    CAS  PubMed  Google Scholar 

  • Hedtjarn M et al (2002) Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci 22(14):5910–5919

    CAS  PubMed  Google Scholar 

  • Heiska L et al (1998) Association of ezrin with intercellular adhesion molecule-1 and −2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. J Biol Chem 273(34):21893–21900

    CAS  PubMed  Google Scholar 

  • Herz J et al (2012) Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions. Neurobiol Dis 45(3):1077–1085

    CAS  PubMed  Google Scholar 

  • Hinkel R et al (2013) Inhibition of MicroRNA-92a protects against ischemia/reperfusion injury in a large-animal model. Circulation 128(10):1066–1075

    CAS  PubMed  Google Scholar 

  • Hirani N et al (2001) The regulation of interleukin-8 by hypoxia in human macrophages–a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). Mol Med 7(10):685–697

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A 95(16):9349–9354

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hitchon C et al (2002) Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 46(10):2587–2597

    CAS  PubMed  Google Scholar 

  • Hogan BM et al (2009) Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet 41(4):396–398

    CAS  PubMed  Google Scholar 

  • Hong KH, Ryu J, Han KH (2005) Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood 105(4):1405–1407

    CAS  PubMed  Google Scholar 

  • Horie N et al (2011) Transplanted stem cell-secreted VEGF effects post-stroke recovery, inflammation, and vascular repair. Stem Cells. doi:10.1002/stem.584

    PubMed Central  PubMed  Google Scholar 

  • Hu F et al (2013) Hypoxia-inducible factor-1alpha and interleukin 33 form a regulatory circuit to perpetuate the inflammation in rheumatoid arthritis. PloS ONE 8(8):e72650

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang RB, Eniola-Adefeso O (2012) Shear stress modulation of IL-1beta-induced E-selectin expression in human endothelial cells. PloS ONE 7(2):e31874

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hubbi ME et al (2013a) Chaperone-mediated autophagy targets hypoxia-inducible factor-1alpha (HIF-1alpha) for lysosomal degradation. J Biol Chem 288(15):10703–10714

    CAS  PubMed  Google Scholar 

  • Hubbi ME, Hu H, Kshitiz GDM, Semenza GL (2013b) Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem 288(29):20768–20775

    CAS  PubMed  Google Scholar 

  • Hull ML et al (2003) Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab 88(6):2889–2899

    CAS  PubMed  Google Scholar 

  • Hullinger TG et al (2012) Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res 110(1):71–81

    CAS  PubMed Central  PubMed  Google Scholar 

  • Iadecola C, Alexander M (2001) Cerebral ischemia and inflammation. Curr Opin Neurol 14(1):89–94

    CAS  PubMed  Google Scholar 

  • Iyer NV et al (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12(2):149–162

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989

    CAS  PubMed  Google Scholar 

  • Janssen BJ et al (2012) Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol 19(12):1293–1299

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jeltsch M, Leppanen VM, Saharinen P, Alitalo K (2013) Receptor tyrosine kinase-mediated angiogenesis. Cold Spring Harb Perspect Biol 5(9). doi:10.1101/cshperspect.a009183

  • Jeong HJ et al (2005) Hypoxia-induced IL-6 production is associated with activation of MAP kinase, HIF-1, and NF-kappaB on HEI-OC1 cells. Hear Res 207(1–2):59–67

    CAS  PubMed  Google Scholar 

  • Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L (2003) IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J Off Publ Fed Am Soc Exp Biol 17(14):2115–2117

    CAS  Google Scholar 

  • Kaipainen A et al (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92(8):3566–3570

    CAS  PubMed Central  PubMed  Google Scholar 

  • Karakurum M et al (1994) Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest 93(4):1564–1570

    CAS  PubMed Central  PubMed  Google Scholar 

  • Karkkainen MJ et al (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5(1):74–80

    CAS  PubMed  Google Scholar 

  • Kastrup J et al (2005) Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol 45(7):982–988

    CAS  PubMed  Google Scholar 

  • Kelly TJ, Souza AL, Clish CB, Puigserver P (2011) A hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1-like. Mol Cell Biol 31(13):2696–2706

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2(10):727–739

    CAS  PubMed  Google Scholar 

  • Kim J et al (2008) Hypoxia-induced IL-18 increases hypoxia-inducible factor-1alpha expression through a Rac1-dependent NF-kappaB pathway. Mol Biol Cell 19(2):433–444

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim JY, Kim N, Zheng Z, Lee JE, Yenari MA (2013) The 70 kDa heat shock protein protects against experimental traumatic brain injury. Neurobiol Dis 58:289–295

    CAS  PubMed  Google Scholar 

  • Kiss J et al (2012) Loss of the oxygen sensor PHD3 enhances the innate immune response to abdominal sepsis. J Immunol 189(4):1955–1965

    CAS  PubMed  Google Scholar 

  • Klement G et al (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105(8):R15–R24

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kotch LE, Iyer NV, Laughner E, Semenza GL (1999) Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol 209(2):254–267

    CAS  PubMed  Google Scholar 

  • Kulshreshtha R, Davuluri RV, Calin GA, Ivan M (2008) A microRNA component of the hypoxic response. Cell Death Differ 15(4):667–671

    CAS  PubMed  Google Scholar 

  • Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M (2012) Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 122(11):4213–4217

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kurokawa M et al (2013) Interleukin-33-activated dendritic cells induce the production of thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Arch Allergy Immunol 161(Suppl 2):52–57

    CAS  PubMed  Google Scholar 

  • Kusumanto YH et al (2006) Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum Gene Ther 17(6):683–691

    CAS  PubMed  Google Scholar 

  • Lee CG et al (2000) Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60(19):5565–5570

    CAS  PubMed  Google Scholar 

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    CAS  PubMed  Google Scholar 

  • Lim JH et al (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell 38(6):864–878

    CAS  PubMed  Google Scholar 

  • Loscalzo J (2010) The cellular response to hypoxia: tuning the system with microRNAs. J Clin Invest 120(11):3815–3817

    CAS  PubMed Central  PubMed  Google Scholar 

  • Makinen K et al (2002) Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol Ther J Am Soc Gene Ther 6(1):127–133

    CAS  Google Scholar 

  • Makino Y et al (2007) Transcriptional up-regulation of inhibitory PAS domain protein gene expression by hypoxia-inducible factor 1 (HIF-1): a negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells. J Biol Chem 282(19):14073–14082

    CAS  PubMed  Google Scholar 

  • Marchant DJ et al (2012) Inflammation in myocardial diseases. Circ Res 110(1):126–144

    CAS  PubMed  Google Scholar 

  • Marsch E, Sluimer JC, Daemen MJ (2013) Hypoxia in atherosclerosis and inflammation. Curr Opin Lipidol 24(5):393–400

    CAS  PubMed  Google Scholar 

  • Marumo T, Schini-Kerth VB, Busse R (1999) Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes 48(5):1131–1137

    CAS  PubMed  Google Scholar 

  • Maynard SE et al (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111(5):649–658

    CAS  PubMed Central  PubMed  Google Scholar 

  • Maynard MA et al (2005) Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J Off Publ Fed Am Soc Exp Biol 19(11):1396–1406

    CAS  Google Scholar 

  • McCormick RI et al (2013) miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. Br J Cancer 108(5):1133–1142

    CAS  PubMed  Google Scholar 

  • McEver RP, Beckstead JH, Moore KL, Marshall-Carlson L, Bainton DF (1989) GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest 84(1):92–99

    CAS  PubMed Central  PubMed  Google Scholar 

  • McLaren J et al (1996) Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 98(2):482–489

    CAS  PubMed Central  PubMed  Google Scholar 

  • Metinko AP, Kunkel SL, Standiford TJ, Strieter RM (1992) Anoxia-hyperoxia induces monocyte-derived interleukin-8. J Clin Invest 90(3):791–798

    CAS  PubMed Central  PubMed  Google Scholar 

  • Miller JW, Le Couter J, Strauss EC, Ferrara N (2013) Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120(1):106–114

    PubMed  Google Scholar 

  • Moussion C, Ortega N, Girard JP (2008) The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PloS ONE 3(10):e3331

    PubMed Central  PubMed  Google Scholar 

  • Murakami M et al (2006) Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Blood 108(6):1849–1856

    CAS  PubMed  Google Scholar 

  • Murdoch C, Muthana M, Lewis CE (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175(10):6257–6263

    CAS  PubMed  Google Scholar 

  • Nimrichter L et al (2008) E-selectin receptors on human leukocytes. Blood 112(9):3744–3752

    CAS  PubMed Central  PubMed  Google Scholar 

  • Noels H, Weber C (2011) Catching up with important players in atherosclerosis: type I interferons and neutrophils. Curr Opin Lipidol 22(2):144–145

    CAS  PubMed  Google Scholar 

  • Oosthuyse B et al (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28(2):131–138

    CAS  PubMed  Google Scholar 

  • Peitsidis P, Agrawal R (2010) Role of vascular endothelial growth factor in women with PCO and PCOS: a systematic review. Reprod BioMed Online 20(4):444–452

    CAS  PubMed  Google Scholar 

  • Pellet-Many C, Frankel P, Jia H, Zachary I (2008) Neuropilins: structure, function and role in disease. Biochem J 411(2):211–226

    CAS  PubMed  Google Scholar 

  • Peng H et al (2012) MicroRNA-31 targets FIH-1 to positively regulate corneal epithelial glycogen metabolism. FASEB J 26(8):3140–3147

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pritchard-Jones RO et al (2007) Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 97(2):223–230

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pulkkinen K, Malm T, Turunen M, Koistinaho J, Yla-Herttuala S (2008) Hypoxia induces microRNA miR-210 in vitro and in vivo ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Lett 582(16):2397–2401

    CAS  PubMed  Google Scholar 

  • Rajagopalan S et al (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 108(16):1933–1938

    CAS  PubMed  Google Scholar 

  • Ramakrishnan S (2011) Hydrogel-siRNA for cancer therapy. Cancer Biol Ther 11(9):849–851

    PubMed Central  PubMed  Google Scholar 

  • Rane S et al (2009) Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ Res 104(7):879–886

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ricciardi A et al (2008) Transcriptome of hypoxic immature dendritic cells: modulation of chemokine/receptor expression. Mol Cancer Res 6(2):175–185

    CAS  PubMed  Google Scholar 

  • Ripa RS et al (2006) Intramyocardial injection of vascular endothelial growth factor-A165 plasmid followed by granulocyte-colony stimulating factor to induce angiogenesis in patients with severe chronic ischaemic heart disease. Eur Heart J 27(15):1785–1792

    CAS  PubMed  Google Scholar 

  • Rius J et al (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453(7196):807–811

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sakurai Y, Ohgimoto K, Kataoka Y, Yoshida N, Shibuya M (2005) Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci U S A 102(4):1076–1081

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M (1996) Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Differ Mol Biol J Am Assoc Cancer Res 7(2):213–221

    CAS  Google Scholar 

  • Sawano A, Takahashi T, Yamaguchi S, Shibuya M (1997) The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochem Biophys Res Commun 238(2):487–491

    CAS  PubMed  Google Scholar 

  • Scannell G et al (1993) Hypoxia induces a human macrophage cell line to release tumor necrosis factor-alpha and its soluble receptors in vitro. J Surg Res 54(4):281–285

    CAS  PubMed  Google Scholar 

  • Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123(9):3664–3671

    CAS  PubMed Central  PubMed  Google Scholar 

  • Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12(12):5447–5454

    CAS  PubMed Central  PubMed  Google Scholar 

  • Senger DR et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219(4587):983–985

    CAS  PubMed  Google Scholar 

  • Shibuya M (2011) Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2(12):1097–1105

    PubMed Central  PubMed  Google Scholar 

  • Shin DH et al (2009) Inhibitor of nuclear factor-kappaB alpha derepresses hypoxia-inducible factor-1 during moderate hypoxia by sequestering factor inhibiting hypoxia-inducible factor from hypoxia-inducible factor 1alpha. FEBS J 276(13):3470–3480

    CAS  PubMed  Google Scholar 

  • Simon MP, Tournaire R, Pouyssegur J (2008) The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J Cell Physiol 217(3):809–818

    CAS  PubMed  Google Scholar 

  • Simons D et al (2011) Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med 15(3):668–678

    CAS  PubMed  Google Scholar 

  • Skuli N et al (2012) Endothelial HIF-2alpha regulates murine pathological angiogenesis and revascularization processes. J Clin Invest 122(4):1427–1443

    CAS  PubMed Central  PubMed  Google Scholar 

  • Smith DF, Galkina E, Ley K, Huo Y (2005) GRO family chemokines are specialized for monocyte arrest from flow. Am J Physiol Heart Circ Physiol 289(5):H1976–H1984

    CAS  PubMed  Google Scholar 

  • Smolich BD et al (2001) The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 97(5):1413–1421

    CAS  PubMed  Google Scholar 

  • Somers WS, Tang J, Shaw GD, Camphausen RT (2000) Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1. Cell 103(3):467–479

    CAS  PubMed  Google Scholar 

  • Son J et al (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496(7443):101–105

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL (2003) Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63(19):6130–6134

    CAS  PubMed  Google Scholar 

  • Sun Y et al (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111(12):1843–1851

    CAS  PubMed Central  PubMed  Google Scholar 

  • Taguchi A et al (2008) Identification of hypoxia-inducible factor-1 alpha as a novel target for miR-17-92 microRNA cluster. Cancer Res 68(14):5540–5545

    CAS  PubMed  Google Scholar 

  • Takahashi M (2013) Role of innate immune system in inflammation and cardiac remodeling after myocardial infarction. Curr Vasc Pharmacol (in press)

  • Takahashi T, Ueno H, Shibuya M (1999) VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18(13):2221–2230

    CAS  PubMed  Google Scholar 

  • Takahashi T, Yamaguchi S, Chida K, Shibuya M (2001) A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J 20(11):2768–2778

    CAS  PubMed Central  PubMed  Google Scholar 

  • Takyar S et al (2013) VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis. J Exp Med 210(10):1993–2010

    CAS  PubMed  Google Scholar 

  • Tanaka H et al (2013) MicroRNA-183 upregulates HIF-1alpha by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells. J Neurooncol 111(3):273–283

    CAS  PubMed  Google Scholar 

  • ten Freyhaus H et al (2011) Hypoxia enhances platelet-derived growth factor signaling in the pulmonary vasculature by down-regulation of protein tyrosine phosphatases. Am J Respir Crit Care Med 183(8):1092–1102

    PubMed  Google Scholar 

  • Tewari R, Choudhury SR, Ghosh S, Mehta VS, Sen E (2012) Involvement of TNFalpha-induced TLR4-NF-kappaB and TLR4-HIF-1alpha feed-forward loops in the regulation of inflammatory responses in glioma. J Mol Med 90(1):67–80

    CAS  PubMed  Google Scholar 

  • Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11(1):72–82

    CAS  PubMed  Google Scholar 

  • Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL (1998) The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12(21):3320–3324

    CAS  PubMed Central  PubMed  Google Scholar 

  • Torii S et al (2011) Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins. Cell Death Differ 18(11):1711–1725

    CAS  PubMed Central  PubMed  Google Scholar 

  • Trayhurn P (2013) Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 93(1):1–21

    CAS  PubMed  Google Scholar 

  • Tuttolomondo A et al (2012) Inflammation in ischemic stroke subtypes. Curr Pharm Des 18(28):4289–4310

    CAS  PubMed  Google Scholar 

  • van den Boorn JG, Dassler J, Coch C, Schlee M, Hartmann G (2013) Exosomes as nucleic acid nanocarriers. Adv Drug Deliv Rev 65(3):331–335

    PubMed  Google Scholar 

  • Wahamaa H et al (2011) High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts. Arthritis Res Ther 13(4):R136

    PubMed Central  PubMed  Google Scholar 

  • Wang Y et al (2009) Regulation of endocytosis via the oxygen-sensing pathway. Nat Med 15(3):319–324

    CAS  PubMed  Google Scholar 

  • Wang C et al (2011a) Underexpressed microRNA-199b-5p targets hypoxia-inducible factor-1alpha in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients. J Gastroenterol Hepatol 26(11):1630–1637

    CAS  PubMed  Google Scholar 

  • Wang F et al (2011b) RACK1 regulates VEGF/Flt1-mediated cell migration via activation of a PI3K/Akt pathway. J Biol Chem 286(11):9097–9106

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y et al (2012) Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1. Proc Natl Acad Sci U S A 109(13):4892–4897

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17(11):1410–1422

    CAS  PubMed  Google Scholar 

  • Wei Y, Schober A, Weber C (2013) Pathogenic arterial remodeling: the good and bad of microRNAs. Am J Physiol Heart Circ Physiol 304(8):H1050–H1059

    CAS  PubMed  Google Scholar 

  • White JR et al (2004) Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis. Genomics 83(1):1–8

    CAS  PubMed  Google Scholar 

  • Winning S, Splettstoesser F, Fandrey J, Frede S (2010) Acute hypoxia induces HIF-independent monocyte adhesion to endothelial cells through increased intercellular adhesion molecule-1 expression: the role of hypoxic inhibition of prolyl hydroxylase activity for the induction of NF-kappa B. J Immunol 185(3):1786–1793

    CAS  PubMed  Google Scholar 

  • Woltmann G, McNulty CA, Dewson G, Symon FA, Wardlaw AJ (2000) Interleukin-13 induces PSGL-1/P-selectin-dependent adhesion of eosinophils, but not neutrophils, to human umbilical vein endothelial cells under flow. Blood 95(10):3146–3152

    CAS  PubMed  Google Scholar 

  • Yang L et al (2005) ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow. Blood 106(2):584–592

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yasuda K et al (2012) Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci U S A 109(9):3451–3456

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zampetaki A, Dudek K, Mayr M (2013) Oxidative stress in atherosclerosis: the role of microRNAs in arterial remodeling. Free Radic Biol Med 64:69–77

    CAS  PubMed  Google Scholar 

  • Zechariah A et al (2013a) Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. Stroke J Cereb Circ 44(6):1690–1697

    CAS  Google Scholar 

  • Zechariah A et al (2013b) Hyperlipidemia attenuates vascular endothelial growth factor-induced angiogenesis, impairs cerebral blood flow, and disturbs stroke recovery via decreased pericyte coverage of brain endothelial cells. Arterioscler Thromb Vasc Biol 33(7):1561–1567

    CAS  PubMed  Google Scholar 

  • Zhang H et al (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283(16):10892–10903

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zheng Z, Yenari MA (2004) Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res 26(8):884–892

    CAS  PubMed  Google Scholar 

  • Zou X et al (2005) PSGL-1 derived from human neutrophils is a high-efficiency ligand for endothelium-expressed E-selectin under flow. Am J Physiol Cell Physiol 289(2):C415–C424

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the following grants, DA012104, DA033881, DA034582, DA031202 and Sparboe Endowment for Women’s Cancer Research.

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Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA

    S. Ramakrishnan & Sabita Roy

  2. Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA

    Vidhu Anand & Sabita Roy

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  1. S. Ramakrishnan
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  2. Vidhu Anand
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Correspondence to S. Ramakrishnan.

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Ramakrishnan, S., Anand, V. & Roy, S. Vascular Endothelial Growth Factor Signaling in Hypoxia and Inflammation. J Neuroimmune Pharmacol 9, 142–160 (2014). https://doi.org/10.1007/s11481-014-9531-7

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