This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brock, T. A. Articles by Senger, D. R. Search for Related Content PubMed PubMed Citation Articles by Brock, T. A. Articles by Senger, D. R.

American Journal of Pathology, Vol 138, 213-221, Copyright © 1991 by American Society for Investigative Pathology

REGULAR ARTICLES

Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells

TA Brock, HF Dvorak and DR Senger
Hypertension Program, University of Alabama, Birmingham, AL 35294.

Vascular permeability factor (VPF), a tumor-secreted heparin-binding protein (Mr approximately 38,000), is responsible for increased vessel permeability and fluid accumulation associated with tumor growth. Vascular permeability factor also promotes the growth of human umbilical vein endothelial cells (EC) and bovine pulmonary ECs in vitro. It is shown for the first time that guinea pig VPF (half-maximal and maximal dose approximately 0.4 and 22 pmol/l (picomolar), respectively), as well as human VPF, are potent stimuli for human ECs resulting in [Ca2+]i increases (maximal three- to fourfold) and inositol triphosphate (IP3) formation. Unlike the maximal responses to thrombin and histamine, the [Ca2+]i response to a maximal VPF dose was preceded by a characteristic 10- to 15-second delay. Guinea pig VPF also selectively increased [Ca2+]i in cultured aortic and pulmonary artery ECs, but not aortic smooth muscle cells, human fibroblasts, or neutrophils. Affinity-purified rabbit antibody (raised to a synthetic peptide representing VPF N-terminal amino acids 1 to 24) adsorbed all vessel permeability-increasing activity, EC growth-promoting activity, and specifically all activity responsible for increasing EC [Ca2+]i. Similar to other mediators that increase [Ca2+]i in cultured ECs, VPF also induced a 200% increase in von Willebrand factor release. Together these data indicate that VPF acts directly on ECs and that rapid cellular events in its in vivo/in vitro actions are likely to involve phospholipase C activation, [Ca2+]i increase, and von Willebrand factor release.

This article has been cited by other articles:

				C. Zhou, H. Chen, F. Lu, H. Sellak, J. A. Daigle, M. F. Alexeyev, Y. Xi, J. Ju, J. A. van Mourik, and S. Wu Cav3.1 ({alpha}1G) controls von Willebrand factor secretion in rat pulmonary microvascular endothelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L833 - L844. [Abstract] [Full Text] [PDF]

				L. Qin, H. Zeng, and D. Zhao Requirement of Protein Kinase D Tyrosine Phosphorylation for VEGF-A165-induced Angiogenesis through Its Interaction and Regulation of Phospholipase C{gamma} Phosphorylation J. Biol. Chem., October 27, 2006; 281(43): 32550 - 32558. [Abstract] [Full Text] [PDF]

				T. Mirzapoiazova, I. Kolosova, P. V. Usatyuk, V. Natarajan, and A. D. Verin Diverse effects of vascular endothelial growth factor on human pulmonary endothelial barrier and migration Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L718 - L724. [Abstract] [Full Text] [PDF]

				H.-W. Cheng, A.F. James, R.R. Foster, J.C. Hancox, and D.O. Bates VEGF Activates Receptor-Operated Cation Channels in Human Microvascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1768 - 1776. [Abstract] [Full Text] [PDF]

				N. S. Dawson, D. C. Zawieja, M. H. Wu, and H. J. Granger Signaling pathways mediating VEGF165-induced calcium transients and membrane depolarization in human endothelial cells FASEB J, May 1, 2006; 20(7): 991 - 993. [Abstract] [Full Text] [PDF]

				D. Jho, D. Mehta, G. Ahmmed, X.-P. Gao, C. Tiruppathi, M. Broman, and A. B. Malik Angiopoietin-1 Opposes VEGF-Induced Increase in Endothelial Permeability by Inhibiting TRPC1-Dependent Ca2 Influx Circ. Res., June 24, 2005; 96(12): 1282 - 1290. [Abstract] [Full Text] [PDF]

				S. Rollin, C. Lemieux, R. Maliba, J. Favier, L. R. Villeneuve, B. G. Allen, S. Soker, N. G. Bazan, Y. Merhi, and M. G. Sirois VEGF-mediated endothelial P-selectin translocation: role of VEGF receptors and endogenous PAF synthesis Blood, May 15, 2004; 103(10): 3789 - 3797. [Abstract] [Full Text] [PDF]

				T. M. Pocock, R. R. Foster, and D. O. Bates Evidence of a role for TRPC channels in VEGF-mediated increased vascular permeability in vivo Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1015 - H1026. [Abstract] [Full Text] [PDF]

				M. E. Daly, A. Makris, M. Reed, and C. E. Lewis Hemostatic Regulators of Tumor Angiogenesis: A Source of Antiangiogenic Agents for Cancer Treatment? J Natl Cancer Inst, November 19, 2003; 95(22): 1660 - 1673. [Abstract] [Full Text] [PDF]

				S. Wu, J. Haynes Jr, J. T. Taylor, B. O. Obiako, J. R. Stubbs, M. Li, and T. Stevens Cav3.1 ({alpha}1G) T-Type Ca2+ Channels Mediate Vaso-Occlusion of Sickled Erythrocytes in Lung Microcirculation Circ. Res., August 22, 2003; 93(4): 346 - 353. [Abstract] [Full Text] [PDF]

				H. Zeng, D. Zhao, S. Yang, K. Datta, and D. Mukhopadhyay Heterotrimeric G{alpha}q/G{alpha}11 Proteins Function Upstream of Vascular Endothelial Growth Factor (VEGF) Receptor-2 (KDR) Phosphorylation in Vascular Permeability Factor/VEGF Signaling J. Biol. Chem., May 30, 2003; 278(23): 20738 - 20745. [Abstract] [Full Text] [PDF]

				A. Serraf, H. Aznag, B. Baudet, H. Detruit, F. Seccatore, M. G. Mazmanian, and C. Planche Pulmonary vascular endothelial growth factor and nitric oxide interaction during total cardiopulmonary bypass in neonatal pigs J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 1050 - 1057. [Abstract] [Full Text] [PDF]

				P. C. Manegold, J. Hutter, S. A. Pahernik, K. Messmer, and M. Dellian Platelet-endothelial interaction in tumor angiogenesis and microcirculation Blood, March 1, 2003; 101(5): 1970 - 1976. [Abstract] [Full Text] [PDF]

				J. W. Breslin, P. J. Pappas, J. J. Cerveira, R. W. Hobson II, and W. N. Duran VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H92 - H100. [Abstract] [Full Text] [PDF]

				K. Amano, H. Matsubara, O. Iba, M. Okigaki, S. Fujiyama, T. Imada, H. Kojima, Y. Nozawa, S. Kawashima, M. Yokoyama, et al. Enhancement of Ischemia-Induced Angiogenesis by eNOS Overexpression Hypertension, January 1, 2003; 41(1): 156 - 162. [Abstract] [Full Text] [PDF]

				S. Koyama, E. Sato, A. Tsukadaira, M. Haniuda, H. Numanami, M. Kurai, S. Nagai, and T. Izumi Vascular endothelial growth factor mRNA and protein expression in airway epithelial cell lines in vitro Eur. Respir. J., December 1, 2002; 20(6): 1449 - 1456. [Abstract] [Full Text] [PDF]

				P L Lip, D C Felmeden, A D Blann, N Matheou, S Thakur, I A Cunliffe, and G Y H Lip Plasma vascular endothelial growth factor, soluble VEGF receptor FLT-1, and von Willebrand factor in glaucoma Br. J. Ophthalmol., November 1, 2002; 86(11): 1299 - 1302. [Abstract] [Full Text] [PDF]

				B.C. Kuenen, M. Levi, J.C.M. Meijers, A.K. Kakkar, V.W.M. van Hinsbergh, P.J. Kostense, H.M. Pinedo, and K. Hoekman Analysis of Coagulation Cascade and Endothelial Cell Activation During Inhibition of Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Pathway in Cancer Patients Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1500 - 1505. [Abstract] [Full Text] [PDF]

				S. Koyama, E. Sato, M. Haniuda, H. Numanami, S. Nagai, and T. Izumi Decreased Level of Vascular Endothelial Growth Factor in Bronchoalveolar Lavage Fluid of Normal Smokers and Patients with Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 1, 2002; 166(3): 382 - 385. [Abstract] [Full Text] [PDF]

				B. C. Kuenen, L. Rosen, E. F. Smit, M. R.N. Parson, M. Levi, R. Ruijter, H. Huisman, M. A. Kedde, P. Noordhuis, W. J.F. van der Vijgh, et al. Dose-Finding and Pharmacokinetic Study of Cisplatin, Gemcitabine, and SU5416 in Patients With Solid Tumors J. Clin. Oncol., March 15, 2002; 20(6): 1657 - 1667. [Abstract] [Full Text] [PDF]

				G. S. Marchand, N. Noiseux, J.-F. Tanguay, and M. G. Sirois Blockade of in vivo VEGF-mediated angiogenesis by antisense gene therapy: role of Flk-1 and Flt-1 receptors Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H194 - H204. [Abstract] [Full Text] [PDF]

				T. Matsumoto and L. Claesson-Welsh VEGF Receptor Signal Transduction Sci. Signal., December 11, 2001; 2001(112): re21 - re21. [Abstract] [Full Text] [PDF]

				A. P. McLaughlin and G. W. De Vries Role of PLCgamma and Ca2+ in VEGF- and FGF-induced choroidal endothelial cell proliferation Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1448 - C1456. [Abstract] [Full Text] [PDF]

				I. Zachary Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1375 - C1386. [Abstract] [Full Text] [PDF]

				I. Zachary and G. Gliki Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family Cardiovasc Res, February 16, 2001; 49(3): 568 - 581. [Abstract] [Full Text] [PDF]

				H. M. W. Verheul, A. S. Jorna, K. Hoekman, H. J. Broxterman, M. F. B. G. Gebbink, and H. M. Pinedo Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets Blood, December 15, 2000; 96(13): 4216 - 4221. [Abstract] [Full Text] [PDF]

				J. P. Braybrooke, K. J. O’Byrne, D. J. Propper, A. Blann, M. Saunders, N. Dobbs, C. Han, J. Woodhull, K. Mitchell, J. Crew, et al. A Phase II Study of Razoxane, an Antiangiogenic Topoisomerase II Inhibitor, in Renal Cell Cancer with Assessment of Potential Surrogate Markers of Angiogenesis Clin. Cancer Res., December 1, 2000; 6(12): 4697 - 4704. [Abstract] [Full Text]

				A. Sahni and C. W. Francis Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation Blood, December 1, 2000; 96(12): 3772 - 3778. [Abstract] [Full Text] [PDF]

				T. M. Pocock, B. Williams, F. E. Curry, and D. O. Bates VEGF and ATP act by different mechanisms to increase microvascular permeability and endothelial [Ca2+]i Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1625 - H1634. [Abstract] [Full Text] [PDF]

				I. Zachary, A. Mathur, S. Yla-Herttuala, and J. Martin Vascular Protection : A Novel Nonangiogenic Cardiovascular Role for Vascular Endothelial Growth Factor Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1512 - 1520. [Abstract] [Full Text] [PDF]

				B. Dankbar, T. Padro, R. Leo, B. Feldmann, M. Kropff, R. M. Mesters, H. Serve, W. E. Berdel, and J. Kienast Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma Blood, April 15, 2000; 95(8): 2630 - 2636. [Abstract] [Full Text] [PDF]

				A. Otani, H. Takagi, H. Oh, K. Suzuma, M. Matsumura, E. Ikeda, and Y. Honda Angiotensin II-Stimulated Vascular Endothelial Growth Factor Expression in Bovine Retinal Pericytes Invest. Ophthalmol. Vis. Sci., April 1, 2000; 41(5): 1192 - 1199. [Abstract] [Full Text]

				K. Arastéh and A. Hannah The Role of Vascular Endothelial Growth Factor (VEGF) in AIDS-Related Kaposi's Sarcoma Oncologist, April 1, 2000; 5(90001): 28 - 31. [Abstract] [Full Text]

				W Li and G Keller VEGF nuclear accumulation correlates with phenotypical changes in endothelial cells J. Cell Sci., January 5, 2000; 113(9): 1525 - 1534. [Abstract] [PDF]

				G. Montrucchio, E. Lupia, E. Battaglia, L. Del Sorbo, M. Boccellino, L. Biancone, G. Emanuelli, and G. Camussi Platelet-Activating Factor Enhances Vascular Endothelial Growth Factor-Induced Endothelial Cell Motility and Neoangiogenesis in a Murine Matrigel Model Arterioscler. Thromb. Vasc. Biol., January 1, 2000; 20(1): 80 - 88. [Abstract] [Full Text] [PDF]

				H. He, V. J. Venema, X. Gu, R. C. Venema, M. B. Marrero, and R. B. Caldwell Vascular Endothelial Growth Factor Signals Endothelial Cell Production of Nitric Oxide and Prostacyclin through Flk-1/KDR Activation of c-Src J. Biol. Chem., August 27, 1999; 274(35): 25130 - 25135. [Abstract] [Full Text] [PDF]

				R. SCALIA, G. BOOTH, and D. J. LEFER Vascular endothelial growth factor attenuates leukocyte–endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide FASEB J, June 1, 1999; 13(9): 1039 - 1046. [Abstract] [Full Text]

				N. Doldi, A. Destefani, A. Gessi, D. Grossi, and A. Ferrari Human albumin enhances expression of vascular endothelial growth factor in cultured human luteinizing granulosa cells: importance in ovarian hyperstimulation syndrome Hum. Reprod., May 1, 1999; 14(5): 1157 - 1159. [Abstract] [Full Text] [PDF]

				A. L. Armesilla, E. Lorenzo, P. Gomez del Arco, S. Martinez-Martinez, A. Alfranca, and J. M. Redondo Vascular Endothelial Growth Factor Activates Nuclear Factor of Activated T Cells in Human Endothelial Cells: a Role for Tissue Factor Gene Expression Mol. Cell. Biol., March 1, 1999; 19(3): 2032 - 2043. [Abstract] [Full Text] [PDF]

				H. m. Wu, Y. Yuan, D. C. Zawieja, J. Tinsley, and H. J. Granger Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H535 - H542. [Abstract] [Full Text] [PDF]

				Y.-X. Chen, Y. Nakashima, K. Tanaka, S. Shiraishi, K. Nakagawa, and K. Sueishi Immunohistochemical Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Atherosclerotic Intimas of Human Coronary Arteries Arterioscler. Thromb. Vasc. Biol., January 1, 1999; 19(1): 131 - 139. [Abstract] [Full Text] [PDF]

				B.-Q. Shen, D. Y. Lee, H.-P. Gerber, B. A. Keyt, N. Ferrara, and T. F. Zioncheck Homologous Up-regulation of KDR/Flk-1 Receptor Expression by Vascular Endothelial Growth Factor in Vitro J. Biol. Chem., November 6, 1998; 273(45): 29979 - 29985. [Abstract] [Full Text] [PDF]

				J. Hood and H. J. Granger Protein Kinase G Mediates Vascular Endothelial Growth Factor-induced Raf-1 Activation and Proliferation in Human Endothelial Cells J. Biol. Chem., September 4, 1998; 273(36): 23504 - 23508. [Abstract] [Full Text] [PDF]

				F. Xu and J. W. Severinghaus Rat brain VEGF expression in alveolar hypoxia: possible role in high-altitude cerebral edema J Appl Physiol, July 1, 1998; 85(1): 53 - 57. [Abstract] [Full Text] [PDF]

				S. Hippenstiel, M. Krull, A. Ikemann, W. Risau, M. Clauss, and N. Suttorp VEGF induces hyperpermeability by a direct action on endothelial cells Am J Physiol Lung Cell Mol Physiol, May 1, 1998; 274(5): L678 - L684. [Abstract] [Full Text] [PDF]

				A. Otani, H. Takagi, K. Suzuma, and Y. Honda Angiotensin II Potentiates Vascular Endothelial Growth Factor–Induced Angiogenic Activity in Retinal Microcapillary Endothelial Cells Circ. Res., March 23, 1998; 82(5): 619 - 628. [Abstract] [Full Text] [PDF]

				J. D. Hood, C. J. Meininger, M. Ziche, and H. J. Granger VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells Am J Physiol Heart Circ Physiol, March 1, 1998; 274(3): H1054 - H1058. [Abstract] [Full Text] [PDF]

				A. Parenti, L. Morbidelli, X.-L. Cui, J. G. Douglas, J. D. Hood, H. J. Granger, F. Ledda, and M. Ziche Nitric Oxide Is an Upstream Signal of Vascular Endothelial Growth Factor-induced Extracellular Signal-regulated Kinase1/2 Activation in Postcapillary Endothelium J. Biol. Chem., February 13, 1998; 273(7): 4220 - 4226. [Abstract] [Full Text] [PDF]

				Y. Wen, J. L. Edelman, T. Kang, N. Zeng, and G. Sachs Two Functional Forms of Vascular Endothelial Growth Factor Receptor-2/Flk-1 mRNA Are Expressed in Normal Rat Retina J. Biol. Chem., January 23, 1998; 273(4): 2090 - 2097. [Abstract] [Full Text] [PDF]

				T. Murohara, J. R. Horowitz, M. Silver, Y. Tsurumi, D. Chen, A. Sullivan, and J. M. Isner Vascular Endothelial Growth Factor/Vascular Permeability Factor Enhances Vascular Permeability Via Nitric Oxide and Prostacyclin Circulation, January 13, 1998; 97(1): 99 - 107. [Abstract] [Full Text] [PDF]

				E. Y. Soh, Q.-Y. Duh, S. A. Sobhi, D. M. Young, H. D. Epstein, M. G. Wong, Y. K. Garcia, Y. D. Min, R. F. Grossman, A. E. Siperstein, et al. Vascular Endothelial Growth Factor Expression Is Higher in Differentiated Thyroid Cancer than in Normal or Benign Thyroid J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3741 - 3747. [Abstract] [Full Text] [PDF]

				J. R. Horowitz, A. Rivard, R. van der Zee, M. Hariawala, D. D. Sheriff, D. D. Esakof, G. M. Chaudhry, J. F. Symes, and J. M. Isner Vascular Endothelial Growth Factor/Vascular Permeability Factor Produces Nitric Oxide–Dependent Hypotension : Evidence for a Maintenance Role in Quiescent Adult Endothelium Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 2793 - 2800. [Abstract] [Full Text]

				C. Y. Cheung Vascular Endothelial Growth Factor: Possible Role in Fetal Development and Placental Function Reproductive Sciences, July 1, 1997; 4(4): 169 - 177. [Abstract] [PDF]

				R. van der Zee, T. Murohara, Z. Luo, F. Zollmann, J. Passeri, C. Lekutat, and J. M. Isner Vascular Endothelial Growth Factor/Vascular Permeability Factor Augments Nitric Oxide Release From Quiescent Rabbit and Human Vascular Endothelium Circulation, February 18, 1997; 95(4): 1030 - 1037. [Abstract] [Full Text]

				Z. Kovacs, K. Ikezaki, K. Samoto, T. Inamura, M. Fukui, T. Kawamata, and S. P. Finklestein VEGF and flt: Expression Time Kinetics in Rat Brain Infarct Stroke, October 1, 1996; 27(10): 1865 - 1873. [Abstract] [Full Text]

				B. Williams, A. Q. Baker, B. Gallacher, and D. Lodwick Angiotensin II Increases Vascular Permeability Factor Gene Expression by Human Vascular Smooth Muscle Cells Hypertension, May 1, 1995; 25(5): 913 - 917. [Abstract] [Full Text]

				W. Roberts and G. Palade Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor J. Cell Sci., January 6, 1995; 108(6): 2369 - 2379. [Abstract] [PDF]

				H. Zeng, S. Sanyal, and D. Mukhopadhyay Tyrosine Residues 951 and 1059 of Vascular Endothelial Growth Factor Receptor-2 (KDR) Are Essential for Vascular Permeability Factor/Vascular Endothelial Growth Factor-induced Endothelium Migration and Proliferation, Respectively J. Biol. Chem., August 24, 2001; 276(35): 32714 - 32719. [Abstract] [Full Text] [PDF]

				H. Zeng, H. F. Dvorak, and D. Mukhopadhyay Vascular Permeability Factor (VPF)/Vascular Endothelial Growth Factor (VEGF) Receptor-1 Down-modulates VPF/VEGF Receptor-2-mediated Endothelial Cell Proliferation, but Not Migration, through Phosphatidylinositol 3-Kinase-dependent Pathways J. Biol. Chem., July 13, 2001; 276(29): 26969 - 26979. [Abstract] [Full Text] [PDF]