p38 Mitogen-activated protein kinase mediates hypoxia-induced vascular endothelial growth factor release in human endothelial cells

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Author:
FAN Bei()
WANG Yan-Xia()
YAO Tai()
ZHU Yi-Chun()
Journal Title:
ACTA PHYSIOLOGICA SINICA
Issue:
Volume 57, Issue 01, 2005
DOI:
Key Word:
hypoxia;vascular endothelial growth factor;vascular endothelial cells;mitogen-activated protein kinase p38;signal transduction

Abstract: Increased vascular endothelial growth factor (VEGF) biosynthesis in vascular endothelial cells has been reported to play an obligatory role in promoting angiogenesis. Nevertheless, the intracellular signaling mechanisms of hypoxia-induced VEGF release remain largely unknown. Human umbilical vein endothelial cell lines (ECV304) were cultured in normoxic or hypoxic conditions for 12~24 h and harvested for determination of VEGF mRNA expression and. phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase (p38 MAPK) by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis,respectively. Secreted VEGF protein was measured by enzyme-linked immunosorbent assay (ELISA). It has reported that PD98059,an ERK inhibitor, was able to blunt the hypoxia-induced activation of the expression of VEGF gene. In accordance with this report, an increase in ERK1/2 phosphorylation and VEGF biosynthesis was observed in ECV304 cells cultured in hypoxia, and this increase was blocked by PD98059. The novel finding of the present study is that an activation of p38 MAPK is involved in hypoxia-induced increase in VEGF biosynthesis. SB202190, an inhibitor of p38 MAPK was able to blunt the hypoxia-induced increase in VEGF biosynthesis. These dada provide the first direct evidence for a role of p38 MAPK in mediating hypoxia-induced increase in VEGF biosynthesis in human endothelial cells.

  • [1]Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 671-674.
  • [2]Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 2001;280: C1358-C1366.
  • [3]Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999; 77: 527-543.
  • [4]Ruhrberg C. Growing and shaping the vascular tree: multiple roles for VEGF. Bioessays 2003; 25:1052-1060.
  • [5]Zhang DZ (张端珍), Gai LY, Chen YW, Fan RY, Wen YF, Dong W. Therapeutic angiogenesis with the use of vascular endothelial growth factor 165 gene in the myocardium of miniature swine.Acta Physiol Sin (生理学报) 2001; 53 (3): 183-187 (Chinese,English abstract).
  • [6]Belgore FM, Blann AD, Li-Saw-Hee FL, Beevers DG, Lip GY.Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension. Am J Cardiol 2001;87: 805-807.
  • [7]Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E. Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc Res 1994; 28:1176-1179.
  • [8]Carmeliet P. Angiogenesis in health and disease. Nat Med 2003;9: 653-660
  • [9]Berra E, Pages G, Pouyssegur J. MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev 2000; 19:139-145.
  • [10]Harry LE, Paleolog EM. From the cradle to the clinic: VEGF in developmental, physiological, and pathological angiogenesis.Birth Defects Res Part C Embryo Today 2003; 69:363-374.
  • [11]Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N. VEGF is required for growth and survival in neonatal mice. Development 1999;126:1149-1159.
  • [12]Marti HH, Risau W. Angiogenesis in ischemic disease. Thromb Haemost 1999; 82: 44-52.
  • [13]Semenza GL. Regulation ofhypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J Clin Invest 2001; 108:39-40.
  • [14]Zhou Z, Yang XM, Xie YZ, Yin ZY. Vascular endothelial growth factor gene expression regulated by protein kinase C pathway in endothelial cells during hypoxia. Space Med Med Eng 2002; 15:322-326.
  • [15]Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359: 843-845.
  • [16]Choi KS, Bae MK, Jeong JW, Moon HE, Kim KW. Hypoxiainduced angiogenesis during carcinogenesis. J Biochem Mol Biol 2003; 36: 120-127.
  • [17]Levy AP, Levy NS, Loscalzo J, Calderone A, Takahashi N, Yeo KT, Koren G, Colucci WS, Goldberg MA. Regulation of vascular endothelial growth factor in cardiac myocytes. Circ Res 1995;76: 758-766.
  • [18]Hata Y, Nakagawa K, Ishibashi T, Inomata H, Ueno H, Sueishi K. Hypoxia-induced expression of vascular endothelial growth factor by retinal glial cells promotes in vitro angiogenesis. Virchows Arch 1995; 426: 479-486.
  • [19]Stavri GT, Hong Y, Zachary IC, Breier G, Baskerville PA, YlaHerttuala S, Risau W, Martin JF, Erusalimsky JD. Hypoxia and platelet-derived growth factor-BB synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells. FEBS Lett 1995; 358:311-315.
  • [20]Shima DT, Deutsch U, D'Amore PA. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett 1995; 370: 203-208.
  • [21]Yang HF (杨海峰), Tang WP. Vascular endothelial growth factor gene expression in nasopharyngeal carcinoma cell line induced by hypoxia in vitro. Chin J Cancer (癌症) 2003; 22:160-163 (Chinese, English abstract).
  • [22]Stein I, Neeman M, Shweiki D, Itin A, Keshet E. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes.Mol Cell Biol 1995; 15: 5363-5368.
  • [23]Mottet D, Michel G, Renard P, Ninane N, Raes M, Michels C.Role of ERK and calcium in the hypoxia-induced activation of HIF-1. J Cell Physiol 2003; 194: 30-44.
  • [24]Chang L, Karin M. Mammalian MAP kinase signalling cascades.Nature 2001; 410: 37-40.
  • [25]Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997; 9: 180-186.
  • [26]Muller JM, Krauss B, Kaltschmidt C, Baeuerle PA, Rupec RA.Hypoxia induces c-fos transcription via a mitogen-activated protein kinase-dependent pathway. J Biol Chem 1997; 272:23435-23439.
  • [27]Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M,Remacle J, Michiels C. ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett 2000; 468: 53-58.
  • [28]Hur E, Chang KY, Lee E, Lee SK, Park H. Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the frans-activation but not the stabilization or DNA binding ability of hypoxiainducible factor-lalpha. Mol Pharmaco12001; 59: 1216-1224.
  • [29]Lazar DF, Wiese R J, Brady M J, Mastick CC, Waters SB,Yamauchi K, Pessin JE, Cuatrecasas P, Saltiel AR. Mitogenactivated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem 1995;270: 20801-20807.
  • [30]Johnson GV, Bailey CD. The p38 MAP kinase signaling pathway in Alzheimer's disease. Exp Neurol 2003; 183: 263-268.
  • [31]Mohamed KM, Le A, Duong H, Wu Y, Zhang Q, Messadi DV.Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma. Exp Mol Pathol 2004; 76:143-152.
  • [32]Poulaki V, Mitsiades CS, McMullan C, Sykoutri D, Fanourakis G, Kotoula V, Tseleni-Balafouta S, Koutras DA, Mitsiades N.Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas. J Clin Endocrinol Metab 2003; 88: 5392-5398.
  • [33]Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD,Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF,Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF,Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L,Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M,Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS,Loquellano NA, Peters GJ, Abramson RD, Mullahy S J, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH,Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW,Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A,Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG,Blakesley RW, Touchman JW, Green ED, Dickson MC,Rodrigue
  • [34]Takahashi K, Sawasaki Y, Hata J, Mukai K, Goto T. Spontaneous transformation and immortalization of human endothelial cells. In vitro Cell Dev Biol 1990; 26(3 Pt 1): 265-274.
  • [35]Liu Y, Cox SR, Morita T, Kourembanas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5' enhancer. Circ Res 1995; 77: 638-643.
  • [36]Levy AP. Hypoxic Regulation of VEGF mRNA Stability by RNA-binding Proteins. Trends Cardiovasc Med 1998; 8: 246-250.
  • [37]Berra E, Milanini J, Richard DE, Le Gall M, Vinals F, Gothie E,Roux D, Pages G, Pouyssegur J. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol 2000; 60:1171-1178.
  • [38]Mukhopadhyay D, Datta K. Multiple regulatory pathways of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in tumors. Semin Cancer Biol 2004; 14:123-130.
  • [39]Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress: the p38 MAPK pathway. Crit Care Med 2000; 28:N67-N77.
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