Skip to main content

Advertisement

SpringerLink
Log in

Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin

  • ORIGINAL ARTICLE
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The aim of this study was to investigate hypoxia effects on vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 in human umbilical vein endothelial cells (HUVEC) and to determine their modulation by the peptide somatostatin (SRIF) and its analogues. The involvement of signal transducer and activator of transcription (STAT) 3 and hypoxia inducible factor (HIF)-1 was also investigated. Quantitative real-time PCR, Western blot and ELISA were used. Hypoxia upregulated VEGF expression and release, whereas it downregulated VEGFR-1 and VEGFR-2. In contrast, neither the expression nor the phosphorylation of the platelet-derived growth factor receptor (PDGFR) β was affected by hypoxia. SU1498 at 1 μM did not affect pVEGFR-2 and pPDGFRβ, whereas at 20 μM it inhibited pVEGFR-2, but not pPDGFRβ. Upregulated VEGF expression and release were prevented by SU1498, which also inhibited the hypoxia-induced pSTAT3 and HIF-1α. Blocking pSTAT3 with S3I-201 inhibited HIF-1α and VEGF upregulation, suggesting the existence of an autocrine loop involving STAT3, HIF-1, VEGF and VEGFR-2. Endothelial cells express somatostatin (SRIF) receptors (sst1–5) although less is known in HUVEC. We found that sst1 and sst4 were expressed by HUVEC with sst1 more expressed than sst4 mRNA. Hypoxia downregulated sst1, whereas it upregulated sst4. The sst1 downregulation, but not the sst4 upregulation, was prevented by SU1498, S3I-201 or YC-1, an inhibitor of HIF-1α. SRIF and the sst1 agonist CH-275, but not the sst4 agonist L803,087 and the sst2/sst3/sst5 agonist octreotide, prevented hypoxia effects on VEGF and its receptors. In addition, SRIF and CH-275 inhibited the hypoxia-induced pSTAT3 and HIF-1α accumulation. Our results suggest that SRIF acting at sst1 limits upregulated VEGF expression and release through a control on the activity of STAT3 and HIF-1, supporting the possible use of sst1 agonists in antiangiogenic therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  • Adams RL, Adams IP, Lindow SW, Atkin SL (2004) Inhibition of endothelial proliferation by the somatostatin analogue SOM230. Clin Endocrinol Oxf 61:431–436

    Article  PubMed  CAS  Google Scholar 

  • Adams RL, Adams IP, Lindow SW, Zhong W, Atkin SL (2005) Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium. Br J Cancer 92:1493–1498

    Article  PubMed  CAS  Google Scholar 

  • Albini A, Florio T, Giunciuglio D, Masiello L, Carlone S, Corsaro A, Thellung S, Cai T, Noonan DM, Schettini G (1999) Somatostatin controls Kaposi’s sarcoma tumor growth through inhibition of angiogenesis. FASEB J 13:647–655

    PubMed  CAS  Google Scholar 

  • Alderton F, Humphrey PP, Sellers LA (2001) High-intensity p38 kinase activity is critical for p21(cip1) induction and the antiproliferative function of G(i) protein-coupled receptors. Mol Pharmacol 59:1119–1128

    PubMed  CAS  Google Scholar 

  • Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, Albuquerque RJ, Richter E, Sakurai E, Newcomb MT, Kleinman ME, Caldwell RB, Lin Q, Ogura Y, Orecchia A, Samuelson DA, Agnew DW, St Leger J, Green WR, Mahasreshti PJ, Curiel DT, Kwan D, Marsh H, Ikeda S, Leiper LJ, Collinson JM, Bogdanovich S, Khurana TS, Shibuya M, Baldwin ME, Ferrara N, Gerber HP, De Falco S, Witta J, Baffi JZ, Raisler BJ, Ambati J (2006) Corneal avascularity is due to soluble VEGF receptor-1. Nature 443:993–997

    Article  PubMed  CAS  Google Scholar 

  • Avouac J, Wipff J, Goldman O, Ruiz B, Couraud PO, Chiocchia G, Kahan A, Boileau C, Uzan G, Allanore Y (2008) Angiogenesis in systemic sclerosis: impaired expression of vascular endothelial growth factor receptor 1 in endothelial progenitor-derived cells under hypoxic conditions. Arthritis Rheum 58:3550–3561

    Article  PubMed  CAS  Google Scholar 

  • Bartoli M, Platt D, Lemtalsi T, Gu X, Brooks SE, Marrero MB, Caldwell RB (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J 17:1562–1564

    PubMed  CAS  Google Scholar 

  • Bocci G, Culler MD, Fioravanti A, Orlandi P, Fasciani A, Colucci R, Taylor JE, Sadat D, Danesi R, Del Tacca M (2007) In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. Eur J Clin 37:700–708

    Article  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Chao TC, Chao HH, Lin JD, Chen MF (1999) Somatostatin and octreotide modulate the function of Kupffer cells in liver cirrhosis. Regul Pept 79:117–124

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Han ZC (2008) STAT3: a critical transcription activator in angiogenesis. Med Res Rev 28:185–200

    Article  PubMed  CAS  Google Scholar 

  • Chen SH, Murphy DA, Lassoued W, Thurston G, Feldman MD, Lee WM (2008) Activated STAT3 is a mediator and biomarker of VEGF endothelial activation. Cancer Biol Ther 7:1994–2003

    Article  PubMed  CAS  Google Scholar 

  • Cho SW, Hartle L, Son SM, Yang F, Goldberg M, Xu Q, Langer R, Anderson DG (2008) Delivery of small interfering RNA for inhibition of endothelial cell apoptosis by hypoxia and serum deprivation. Biochem Biophys Res Commun 376:158–163

    Article  PubMed  CAS  Google Scholar 

  • Chun YS, Yeo EJ, Choi E, Teng CM, Bae JM, Kim MS, Park JW (2001) Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochem Pharmacol 61:947–954

    Article  PubMed  CAS  Google Scholar 

  • Cresci B, Giannini S, Pala L, Mavilia C, Manuelli C, Cappugi P, Maggi E, Rotella CM (2003) AT1 and AT2 receptors in human glomerular endothelial cells at different passages. Microvasc Res 66:22–29

    Article  PubMed  CAS  Google Scholar 

  • Cui R, Takahashi F, Ohashi R, Yoshioka M, Gu T, Tajima K, Unnoura T, Iwakami S, Hirama M, Ishiwata T, Iwase A, Takahashi K (2009) Osteopontin is involved in the formation of malignant pleural effusion in lung cancer. Lung Cancer 63:368–374

    Article  PubMed  Google Scholar 

  • Cummins EP, Taylor CT (2005) Hypoxia-responsive transcription factors. Pflugers Arch 450:363–371

    Article  PubMed  CAS  Google Scholar 

  • Curtis SB, Hewitt J, Yakubovitz S, Anzarut A, Hsiang YN, Buchan AM (2000) Somatostatin receptor subtype expression and function in human vascular tissue. Am J Physiol Heart Circ Physiol 278:H1815–H1822

    PubMed  CAS  Google Scholar 

  • Dal Monte M, Ristori C, Cammalleri M, Bagnoli P (2009) Effects of somatostatin analogues on retinal angiogenesis in a mouse model of oxygen-induced retinopathy: involvement of the somatostatin receptor subtype 2. Invest Ophthalmol Vis Sci 50:3596–3606

    Article  PubMed  Google Scholar 

  • Dal Monte M, Ristori C, Videau C, Loudes C, Martini D, Casini G, Epelbaum J, Bagnoli P (2010) Expression, localization, and functional coupling of the somatostatin receptor subtype 2 in a mouse model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 51:1848–1856

    Article  PubMed  Google Scholar 

  • Danesi R, Agen C, Benelli U, Paolo AD, Nardini D, Bocci G, Basolo F, Campagni A, Del Tacca M (1997) Inhibition of experimental angiogenesis by the somatostatin analogue octreotide acetate (SMS 201-995). Clin Cancer Res 3:265–272

    PubMed  CAS  Google Scholar 

  • Dasgupta P (2004) Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther 102:61–85

    Article  PubMed  CAS  Google Scholar 

  • DeNiro M, Alsmadi O, Al-Mohanna F (2009) Modulating the hypoxia-inducible factor signaling pathway as a therapeutic modality to regulate retinal angiogenesis. Exp Eye Res 89:700–717

    Article  PubMed  CAS  Google Scholar 

  • Deudero JJ, Caramelo C, Castellanos MC, Neria F, Fernández-Sánchez R, Calabia O, Peñate S, González-Pacheco FR (2008) Induction of hypoxia-inducible factor 1alpha gene expression by vascular endothelial growth factor. J Biol Chem 283:11435–11444

    Article  PubMed  CAS  Google Scholar 

  • Di Stefano R, Barsotti MC, Armani C, Santoni T, Lorenzet R, Balbarini A, Celi A (2009) Human peripheral blood endothelial progenitor cells synthesize and express functionally active tissue factor. Thromb Res 123:925–930

    Article  PubMed  Google Scholar 

  • Drenkard D, Becke FM, Langstein J, Spruss T, Kunz-Schughart LA, Tan TE, Lim YC, Schwarz H (2007) CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity. FASEB J 21:456–463

    Article  PubMed  CAS  Google Scholar 

  • Eltzschig HK, Köhler D, Eckle T, Kong T, Robson SC, Colgan SP (2009) Central role of Sp1-regulated CD39 in hypoxia/ischemia protection. Blood 113:224–232

    Article  PubMed  CAS  Google Scholar 

  • Feoktistov I, Ryzhov S, Zhong H, Goldstein AE, Matafonov A, Zeng D, Biaggioni I (2004) Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. Hypertension 44:649–654

    Article  PubMed  CAS  Google Scholar 

  • Florio T, Yao H, Carey KD, Dillon TJ, Stork PJ (1999) Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). Mol Endocrinol 13:24–37

    Article  PubMed  CAS  Google Scholar 

  • Florio T, Morini M, Villa V, Arena S, Corsaro A, Thellung S, Culler MD, Pfeffer U, Noonan DM, Schettini G, Albini A (2003) Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology 144:1574–1584

    Article  PubMed  CAS  Google Scholar 

  • Fong GH (2009) Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med 87:549–560

    Article  PubMed  CAS  Google Scholar 

  • Gariboldi MB, Ravizza R, Monti E (2010) The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells. Biochem Pharmacol 80:455–462

    Article  PubMed  CAS  Google Scholar 

  • Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667

    Article  PubMed  CAS  Google Scholar 

  • Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE (2005) HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24:3110–3120

    Article  PubMed  CAS  Google Scholar 

  • Hannon JP, Nunn C, Stolz B, Bruns C, Weckbecker G, Lewis I, Troxler T, Hurth K, Hoyer D (2002) Drug design at peptide receptors: somatostatin receptor ligands. J Mol Neurosci 18:15–27

    Article  PubMed  CAS  Google Scholar 

  • Hashioka S, Klegeris A, Qing H, McGeer PL (2011) STAT3 inhibitors attenuate interferon-γ-induced neurotoxicity and inflammatory molecule production by human astrocytes. Neurobiol Dis 41:299–307

    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 USA 95:9349–9354

    Article  PubMed  CAS  Google Scholar 

  • Hofland LJ, Lamberts SW (2001) Somatostatin receptor subtype expression in human tumors. Ann Oncol 12(Suppl 2):S31–S36

    Article  PubMed  Google Scholar 

  • Horiguchi A, Asano T, Kuroda K, Sato A, Asakuma J, Ito K, Hayakawa M, Sumitomo M, Asano T (2010) STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. Br J Cancer 102:1592–1599

    Article  PubMed  CAS  Google Scholar 

  • Hsu HK, Juan SH, Ho PY, Liang YC, Lin CH, Teng CM, Lee WS (2003) YC-1 inhibits proliferation of human vascular endothelial cells through a cyclic GMP-independent pathway. Biochem Pharmacol 66:263–271

    Article  PubMed  CAS  Google Scholar 

  • Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16:771–780

    Article  PubMed  CAS  Google Scholar 

  • Jia WD, Xu GL, Xu RN, Sun HC, Wang L, Yu JH, Wang J, Li JS, Zhai ZM, Xue Q (2003) Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts. J Cancer Res Clin Oncol 129:327–334

    Article  PubMed  CAS  Google Scholar 

  • Jiang J, Xia XB, XU HZ, Xiong Ym, Song WT, Xiong SQ, Li Y (2009) Inhibition of retinal neovascularization by gene transfer of small interfering RNA targeting HIF-1α and VEGF. J Cell Physiol 218:66–74

    Article  PubMed  CAS  Google Scholar 

  • Jung JE, Lee HG, Cho IH, Chung DH, Yoon SH, Yang YM, Lee JW, Choi S, Park JW, Ye SK, Chung MH (2005) STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J 19:1296–1298

    PubMed  CAS  Google Scholar 

  • Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH, Kim TY, Juhnn YS, Kim SJ, Park JW, Ye SK, Chung MH (2008) STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination. Exp Mol Med 40:479–485

    Article  PubMed  CAS  Google Scholar 

  • Kim JH, Park SH, Park SK, Choi JS, Xia Y, Sung JH (2011) The pivotal role of reactive oxygen species generation in the hypoxia-induced stimulation of adipose-derived stem cells. Stem Cells Dev. doi:10.1089/scd.2010.0469

    Google Scholar 

  • Lang SA, Schachtschneider P, Moser C, Mori A, Hackl C, Gaumann A, Batt D, Schlitt HJ, Geissler EK, Stoeltzing O (2008) Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther 7:3509–3518

    Article  PubMed  CAS  Google Scholar 

  • Lanner MC, Raper M, Pratt WM, Rhoades RA (2005) Heterotrimeric G proteins and the platelet-derived growth factor receptor-beta contribute to hypoxic proliferation of smooth muscle cells. Am J Respir Cell Mol Biol 33:412–419

    Article  PubMed  CAS  Google Scholar 

  • Li M, Li W, Kim HJ, Yao Q, Chen C, Fisher WE (2004) Characterization of somatostatin receptor expression in human pancreatic cancer using real-time RT-PCR. J Surg Res 119:130–137

    Article  PubMed  CAS  Google Scholar 

  • Lin CM, Shyu KG, Wang BW, Chang H, Chen YH, Chiu JH (2010) Chrysin suppresses IL-6-induced angiogenesis via down-regulation of JAK1/STAT3 and VEGF: an in vitro and in ovo approach. J Agric Food Chem 58:7082–7087

    Article  PubMed  CAS  Google Scholar 

  • Liu S, Wu P, Ye D, Huang Y, Zhou X, Li Y, Cai L (2009) Effects of lipoxin A(4) on CoCl(2)-induced angiogenesis and its possible mechanisms in human umbilical vein endothelial cells. Pharmacology 84:17–23

    Article  PubMed  CAS  Google Scholar 

  • Liu C, Dou K, Dou C, Liu J, Zhao Q (2010) Anti-inflammatory effects of tacrolimus in a rat model of acute pancreatitis. Med Chem 6:37–43

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • Lohela M, Bry M, Tammela T, Alitalo K (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21:154–165

    Article  PubMed  CAS  Google Scholar 

  • Lu W, Chen H, Yel F, Wang F, Xie X (2006) VEGF induces phosphorylation of STAT3 through binding VEGFR2 in ovarian carcinoma cells in vitro. Eur J Gynaecol Oncol 27:363–369

    PubMed  CAS  Google Scholar 

  • Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A, Takahashi H, Wakasugi T, Takeyama H (2009) PTEN regulates angiogenesis through PI3K/Akt/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem 331:161–171

    Article  PubMed  CAS  Google Scholar 

  • Mathews MT, Berk BC (2008) PARP-1 inhibition prevents oxidative and nitrosative stress-induced endothelial cell death via transactivation of the VEGF receptor 2. Arterioscler Thromb Vasc Biol 28:711–717

    Article  PubMed  CAS  Google Scholar 

  • Mu H, Ohashi R, Yan S, Chai H, Yang H, Lin P, Yao Q, Chen C (2006) Adipokine resistin promotes in vitro angiogenesis of human endothelial cells. Cardiovasc Res 70:146–157

    Article  PubMed  CAS  Google Scholar 

  • Nilsson I, Shibuya M, Wennström S (2004) Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 299:476–485

    Article  PubMed  CAS  Google Scholar 

  • Nussenbaum F, Herman IM (2010) Tumor angiogenesis: insights and innovations. J Oncol 2010:132641

    PubMed  Google Scholar 

  • Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W (2004) Regulation and function of somatostatin receptors. J Neurochem 89:1057–1091

    Article  PubMed  CAS  Google Scholar 

  • Oomen SP, Ward AC, Hofland LJ, Lamberts SW, Lowenberg B, Touw IP (2001) Somatostatin modulates G-CSF-induced but not interleukin-3-induced proliferative responses in myeloid 32D cells via activation of somatostatin receptor subtype 2. Hematol J 2:322–329

    Article  PubMed  CAS  Google Scholar 

  • Ootsuka S, Asami S, Sasaki T, Yoshida Y, Nemoto N, Shichino H, Chin M, Mugishima H, Suzuki T (2007) Analyses of novel prognostic factors in neuroblastoma patients. Biol Pharm Bull 30:2294–2299

    Article  PubMed  CAS  Google Scholar 

  • Palii SS, Afzal A, Shaw LC, Pan H, Caballero S, Miller RC, Jurczyk S, Reubi JC, Tan Y, Hochhaus G, Edelhauser H, Geroski D, Shapiro G, Grant MB (2008) Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor. Invest Ophthalmol Vis Sci 49:5094–5102

    Article  PubMed  Google Scholar 

  • Park SJ, Kim HY, Kim H, Park SM, Joe EH, Jou I, Choi YH (2009) Oxidative stress induces lipid-raft-mediated activation of Src homology 2 domain-containing protein-tyrosine phosphatase 2 in astrocytes. Free Radic Biol Med 46:1694–1702

    Article  PubMed  CAS  Google Scholar 

  • Patterson C, Perrella MA, Endege WO, Yoshizumi M, Lee ME, Haber E (1996) Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-alpha in cultured human vascular endothelial cells. J Clin Invest 98:490–496

    Article  PubMed  CAS  Google Scholar 

  • Pearlstein DP, Ali MH, Mungai PT, Hynes KL, Gewertz BL, Schumacker PT (2002) Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia. Arterioscler Thromb Vasc Biol 22:566–573

    Article  PubMed  CAS  Google Scholar 

  • Perez J, Viollet C, Doublier S, Videau C, Epelbaum J, Baud L (2003) Somatostatin binds to murine macrophages through two distinct subsets of receptors. J Neuroimmunol 138:38–44

    Article  PubMed  CAS  Google Scholar 

  • Petersenn S, Rasch AC, Presch S, Beil FU, Schulte HM (2002) Characterization of the human somatostatin receptor type 4 promoter. Mol Cell Endocrinol 188:75–83

    Article  PubMed  CAS  Google Scholar 

  • Reinmuth N, Liersch R, Raedel M, Fehrmann F, Fehrmann N, Bayer M, Schwoeppe C, Kessler T, Berdel W, Thomas M, Mesters RM (2009) Combined anti-PDGFRalpha and PDGFRbeta targeting in non-small cell lung cancer. Int J Cancer 124:1535–1544

    Article  PubMed  CAS  Google Scholar 

  • Reubi JC, Horisberger U, Laissue J (1994) High density of somatostatin receptors in veins surrounding human cancer tissue: role in tumor–host interaction? Int J Cancer 56:681–688

    Article  PubMed  CAS  Google Scholar 

  • Reubi JC, Waser B, Schaer JC, Laissue JA (2001) Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 28:836–846

    Article  PubMed  CAS  Google Scholar 

  • Rocha A, Azevedo I, Soares R (2007) Anti-angiogenic effects of imatinib target smooth muscle cells but not endothelial cells. Angiogenesis 10:279–286

    Article  PubMed  CAS  Google Scholar 

  • Sarkanen JR, Mannerström M, Vuorenpää H, Uotila J, Ylikomi T, Heinonen T (2011) Intra-laboratory pre-validation of a human cell based in vitro angiogenesis assay for testing angiogenesis modulators. Front Pharmacol 1:147

    Google Scholar 

  • Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560

    Article  PubMed  CAS  Google Scholar 

  • Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, Sebti SM, Turkson J (2007) Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 104:7391–7396

    Article  PubMed  CAS  Google Scholar 

  • Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK (1996) Flk-1 as a target for tumor growth inhibition. Cancer Res 56:3540–3545

    PubMed  CAS  Google Scholar 

  • Takata K, Morishige K, Takahashi T, Hashimoto K, Tsutsumi S, Yin L, Ohta T, Kawagoe J, Takahashi K, Kurachi H (2008) Fasudil-induced hypoxia-inducible factor-1alpha degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells. Mol Cancer Ther 7:1551–1561

    Article  PubMed  CAS  Google Scholar 

  • Tanaka S, Arii S (2006) Current status and perspective of antiangiogenic therapy for cancer: hepatocellular carcinoma. Int J Clin Oncol 11:82–89

    Article  PubMed  CAS  Google Scholar 

  • Waltenberger J, Mayr U, Pentz S, Hombach V (1996) Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94:1647–1654

    PubMed  CAS  Google Scholar 

  • Wang M, Tan J, Coffey A, Fehrenbacher J, Weil BR, Meldrum DR (2009) Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha-induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg 138:163–171

    Article  PubMed  CAS  Google Scholar 

  • Watson JC, Balster DA, Gebhardt BM, O’Dorisio TM, O’Dorisio MS, Espenan GD, Drouant GJ, Woltering EA (2001) Growing vascular endothelial cells express somatostatin subtype 2 receptors. Br J Cancer 85:266–272

    Article  PubMed  CAS  Google Scholar 

  • Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2:999–1017

    Article  PubMed  CAS  Google Scholar 

  • Woltering EA (2003) Development of targeted somatostatin-based antiangiogenic therapy: a review and future perspectives. Cancer Biother Radiopharm 18:601–609

    Article  PubMed  CAS  Google Scholar 

  • Wyler von Ballmoos M, Yang Z, Völzmann J, Baumgartner I, Kalka C, Di Santo S (2010) Endothelial progenitor cells induce a phenotype shift in differentiated endothelial cells towards PDGF/PDGFRβ axis-mediated angiogenesis. PLoS ONE 5:e14107

    Article  PubMed  Google Scholar 

  • Xu Q, Ji YS, Schmedtje JF Jr (2000) Sp1 increases expression of cyclooxygenase-2 in hypoxic vascular endothelium. Implications for the mechanisms of aortic aneurysm and heart failure. J Biol Chem 275:24583–24589

    Article  PubMed  CAS  Google Scholar 

  • Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, Gritsko T, Turkson J, Kay H, Semenza GL, Cheng JQ, Jove R, Yu H (2005) Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24:5552–5560

    Article  PubMed  CAS  Google Scholar 

  • Yang XP, Irani K, Mattagajasingh S, Dipaula A, Khanday F, Ozaki M, Fox-Talbot K, Baldwin WM 3rd, Becker LC (2005) Signal transducer and activator of transcription 3alpha and specificity protein 1 interact to upregulate intercellular adhesion molecule-1 in ischemic–reperfused myocardium and vascular endothelium. Arterioscler Thromb Vasc Biol 25:1395–1400

    Article  PubMed  CAS  Google Scholar 

  • Yoshie M, Miyajima E, Kyo S, Tamura K (2009) Stathmin, a microtubule regulatory protein, is associated with hypoxia-inducible factor-1alpha levels in human endometrial and endothelial cells. Endocrinology 150:2413–2418

    Article  PubMed  CAS  Google Scholar 

  • Zatelli MC, Piccin D, Vignali C, Tagliati F, Ambrosio MR, Bondanelli M, Cimino V, Bianchi A, Schmid HA, Scanarini M, Pontecorvi A, De Marinis L, Maira G, degli Uberti EC (2007) Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer 14:91–102

    Article  PubMed  CAS  Google Scholar 

  • Zeng H, Dvorak HF, Mukhopadhyay D (2001) Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem 276:26969–26979

    Article  PubMed  CAS  Google Scholar 

  • Zheng X, Zhang S, Yang Y, Wang X, Zhong L, Yu X (2008) The targeting expression of the vascular endothelial growth factor gene in endothelial cells regulated by HRE.ppET-1. Sci China C Life Sci 51:959–965

    Article  PubMed  CAS  Google Scholar 

  • Zhong XS, Zheng JZ, Reed E, Jiang BH (2004) SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem Biophys Res Commun 324:471–480

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from The International Retinal Research Foundation, Inc., (Birmingham, AL, USA) to MDM. The authors wish to thank Dr. Davide Cervia for his collaboration in the early stages of this work.

Author information

Authors and Affiliations

  1. Department of Biology, University of Pisa, via San Zeno, 31, 56127, Pisa, Italy

    Massimo Dal Monte, Davide Martini, Chiara Ristori, Danilo Azara & Paola Bagnoli

  2. Cardiac, Thoracic and Vascular Department, University of Pisa, via Paradisa 2, 56124, Pisa, Italy

    Chiara Armani & Alberto Balbarini

Authors
  1. Massimo Dal Monte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Davide Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Ristori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Danilo Azara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chiara Armani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alberto Balbarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paola Bagnoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Bagnoli.

Additional information

Massimo Dal Monte and Davide Martini contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dal Monte, M., Martini, D., Ristori, C. et al. Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin. Naunyn-Schmiedeberg's Arch Pharmacol 383, 593–612 (2011). https://doi.org/10.1007/s00210-011-0625-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-011-0625-y

Keywords

Search

Navigation