Skip to main content
SpringerLink
Log in

Vascular permeability factor/vascular endothelial growth factor:A multifunctional angiogenic cytokine

  • Chapter
Regulation of Angiogenesis

Part of the book series: Experientia Supplementum ((EXS,volume 79))

Abstract

Vascular permeability factor (VPF), variously known as a vascular endothelial growth factor (VEGF) and vasculotropin (VAS), is a multifunctional cytokine with important roles in vasculogenesis and both pathological and physiological angiogenesis. Originally described in the late 1970s as a tumor-secreted protein that potently increased microvascular permeability to plasma proteins, VPF/VEGF (as we will designate the molecule in this review) exerts a variety of effects on vascular endothelial cells which together promote the formation and growth of new blood vessels. Thus, in addition to rendering microvessels hyperpermeable, VPF/VEGF stimulates endothelial cells to migrate and divide and profoundly alters their pattern of gene expression.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adamis, A., Shima, D., Yeo, K.-T, Yeo, T.-K., Brown, K., Berse, B., D’Amore, P. and Folkman, J. (1993) Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem. Biophys. Res. Comm. 193:631–638.

    PubMed  CAS  Google Scholar 

  • Adamis, A.P., Miller, J.W., Bernal, M.T., D’Amico, D.J., Folkman, J., Yeo, T.K. and Yeo, K.T. (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118:445–450.

    PubMed  CAS  Google Scholar 

  • Aiello, L.P., Avery, R.L., Arrigg, P.G., Keyt, B.A., Jampel, H.D., Shah, ST., Pasquale, L.R., Thieme, H., Iwamoto, M.A., Park, J.E., Nguyen, M.S., Aiello, L.M., Ferrara, N. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331:1480–1487.

    PubMed  CAS  Google Scholar 

  • Alon, T., Hemo, I., Itin, A., Pe’er, J., Stone, J. and Keshet, E. (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Medicine 1:1024–1028.

    PubMed  CAS  Google Scholar 

  • Asahara, T., Bauters, C, Pastore, C, Kearney, M., Rossow, S., Bunting, S., Ferrara, N., Symes, J.F. and Isner, J.M. (1995) Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimai hyperplasia in balloon-injured rat carotid artery. Circulation 91:2793–2801.

    PubMed  CAS  Google Scholar 

  • Banai, S., Jaklitsch, M.T., Shou, M., Lazarous, D.F., Scheinowitz, M., Biro, S., Epstein, S.E. and Unger, E.F. (1994 a) Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 89:2183–2189.

    PubMed  CAS  Google Scholar 

  • Banai, S.D., Shweiki, A., Pinson, M., Chandra, G., Lazarovici, G. and Keshet, E. (1994b) Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc. Res. 28:1176–1179.

    PubMed  CAS  Google Scholar 

  • Barleon, B., Hauser, S., Schollmann, C., Weindel, K., Marme, D., Yayon, A. and Weich, H.A. (1994) Differential expression of the two VEGF receptors fit and KDR in placenta and vascular endothelial cells. J. Cell Biochem. 54:56–66.

    PubMed  CAS  Google Scholar 

  • Bauters, C., Asahara, T., Zheng, L.P, Takeshita, S., Bunting, S., Ferrara, N., Symes, J.F. and Isner, J.M. (1994) Physiological assessment of augmented vascularity induced by VEGF in ischemic rabbit hindlimb. Am. J. Physiol. 267:h1263–1271.

    PubMed  CAS  Google Scholar 

  • Bauters, C., Asahara, T, Zheng, L.P, Takeshita, S., Bunting, S., Ferrara, N., Symes, J.F. and Isner, J.M. (1995 a) Recovery of disturbed endothelium-dependent flow in the collateral-perfused rabbit ischemic hindlimb after administration of vascular endothelial growth factor. Circulation 91:2802–2809.

    PubMed  CAS  Google Scholar 

  • Bauters, C, Asahara, T., Zheng, L.P, Takeshita, S., Bunting, S., Ferrara, N., Symes, J.F. and Isner, J.M. (1995 b) Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor. J. Vase. Surg. 21:314–324.

    CAS  Google Scholar 

  • Berkman, R.A., Merrill, M.J., Reinhold, WC., Monacci, W.T., Saxena, A., Clark, W.C., Robertson, J.T., Ali, I.U. and Oldfield, E.H. (1993) Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J. Clin. Invest. 91:153–159.

    PubMed  CAS  Google Scholar 

  • Berridge, M.J. (1993) Inositol trisphosphate and calcium signalling. Nature 361:315–325.

    PubMed  CAS  Google Scholar 

  • Berse, B., Brown, L.F., Van De Water, L., Dvorak, H.F. and Senger, D.R. (1992) Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol. Biol. Cell 3:211–220.

    PubMed  CAS  Google Scholar 

  • Boucher, Y., Kirkwood, J.M., Opacic, D., Desantis, M. and Jain, R.K. (1991) Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 51:6691–6694.

    PubMed  CAS  Google Scholar 

  • Breier, G., Albrecht, U., Sterrer, S. and Risau, W (1992) Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114:521–532.

    PubMed  CAS  Google Scholar 

  • Brock, T.A., Dvorak, H.F, Senger, D.R. (1991) Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am. J. Pathol. 138:213–221.

    PubMed  CAS  Google Scholar 

  • Brogi, E., Wu, T, Namiki, A. and Isner, J.M. (1994) Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 90:649–652.

    PubMed  CAS  Google Scholar 

  • Brown, L.F, Asch, B., Harvey, VS., Buchinsky, B. and Dvorak, H.F. (1988$20a) Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas. Cancer Res. 48:1920–1925.

    PubMed  CAS  Google Scholar 

  • Brown, L.F, Van De Water, L., Harvey, VS. and Dvorak, H.F. (1988$20b) Fibrinogen influx and accumulation of cross-linked fibrin in healing wounds and in tumor stroma. Am. J. Pathol. 130:455–465.

    PubMed  CAS  Google Scholar 

  • Brown, L.F, Yeo, K.-T, Berse, B., Yeo, T.-K., Senger, D.R., Dvorak, H.F. and Van De Water, L. (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J. Exp. Med. 176:1375–1379.

    PubMed  CAS  Google Scholar 

  • Brown, L.F., Berse, B., Jackman, R.W., Tognazzi, K., Manseau, E.J., Dvorak, H.F. and Senger, D.R. (1993 a). Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am. J. Pathol. 143: 1255–1262.

    PubMed  CAS  Google Scholar 

  • Brown, L.F, Berse, B., Jackman, R.W., Tognazzi, K., Manseau, E.J., Senger, D.R. and Dvorak, H.F. (1993 b) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res. 53:4727–4735.

    PubMed  CAS  Google Scholar 

  • Brown, L.F, Lanir, N., McDonagh, J., Czarnecki, K., Estrella, P., Dvorak, A.M. and Dvorak, H.F. (1993 c) Fibroblast migration in fibrin gel matrices. Am. J. Pathol. 142:273–283.

    PubMed  CAS  Google Scholar 

  • Brown, L., Berse, B., Jackman, R., Tognazzi, K., Guidi, A., Dvorak, H., Senger, D, Connolly, J. and Schnitt, S. (1995) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum. Pathol. 26:86–91.

    PubMed  CAS  Google Scholar 

  • Brown, L., Tognazzi, K., Dvorak, H. and Harrist, T. (1996) Strong expression of KDR, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi’s sarcoma and cutaneous angiosarcoma. Am. J. Pathol. 148:1065–1074.

    PubMed  CAS  Google Scholar 

  • Brown, L., Yeo, K.-T., Berse, B., Morgentaler, A., Dvorak, H. and Rosen, S. (1995 c) Vascular permeability factor (vascular endothelial growth factor) is strongly expressed in the normal male genital tract and is present in substantial quantities in semen. J. Urology 154:576–579.

    CAS  Google Scholar 

  • Brown, L.F., Harrist, T.J., Yeo, K.T., Stahle, B.M., Jackman, R.W., Berse, B., Tognazzi, K., Dvorak, H.F. and Detmar, M. (1995d) Increased expression of vascular permeability factor (vascular endothelial growth factor) in bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme. J. Invest. Dermatol. 104:744–749.

    PubMed  CAS  Google Scholar 

  • Brown, L.F., Ulbricht, S.M., Berse, B., Jackman, R.W., Matsueda, G., Tognazzi, K.A., Manseau, E.J., Dvorak, H.F. and Van De Water, L. (1995e) Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions. J. Immunol. 154:2801–2807.

    PubMed  CAS  Google Scholar 

  • Burke, P.A., Lehmann, B.K. and Powell, J.S. (1995) Vascular endothelial growth factor causes endothelial proliferation after vascular injury. Biochem. Biophys. Res. Commun. 207:348–354.

    PubMed  CAS  Google Scholar 

  • Callow, A.D., Choi, E.T., Trachtenberg, J.D., Stevens, S.L., Connolly, D.T., Rodi, C. and Ryan, U.S. (1994) Vascular permeability factor accelerates endothelial regrowth following balloon angioplasty. Growth Factors 10:223–228.

    PubMed  CAS  Google Scholar 

  • Charnock-Jones, D., Sharkey, A., Rajput, W.J., Burch, D., Schofield, J.P., Fountain, S.A., Boocock, C.A. and Smith, S.K. (1993) Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol. Reprod. 48:1120–1128.

    PubMed  CAS  Google Scholar 

  • Charnock-Jones, D., Sharkey, A., Boocock, C, Ahmed, A., Plevin, R., Ferrara, N. and Smith, S. (1994) Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol. Reprod. 51:524–530.

    PubMed  CAS  Google Scholar 

  • Christofori, G., Naik, P. and Hanahan, D. (1995) Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol. Endocrinol. 9:1760–1770.

    PubMed  CAS  Google Scholar 

  • Claffey, K.P., Wilkison, W.O. and Spiegelman, B.M. (1992) Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J. Biol. Chem. 267:16317–16322.

    CAS  Google Scholar 

  • Claffey, K.P., Senger, D.R. and Spiegelman, B.M. (1995) Structural requirements for dimerization, glycosylation, secretion, and biological function of VPF/VEGF. Biochim. Biophys. Acta 1246:1–9.

    PubMed  Google Scholar 

  • Clauss, M., Gerlach, M., Gerlach, H., Brett, J., Wang, F, Familletti, P.C., Pan, Y.-C.E., Olander, J.V, Connolly, D.T. and Stern, D. (1990) Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J. Exp. Med. 172:1535–1545.

    PubMed  CAS  Google Scholar 

  • Cohen, T., Gitay, G.H., Sharon, R., Shibuya, M., Halaban, R., Levi, B.Z. and Neufeld, G. (1995) VEGF 121, 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. 270:11322–11326.

    PubMed  CAS  Google Scholar 

  • Collins, P.D., Connolly, D.T. and Williams, T.J. (1993) Characterization of the increase in vascular permeability induced by vascular permeability factor in vivo. Br. J. Pharmacol. 109:195–199.

    PubMed  CAS  Google Scholar 

  • Conn, G., Bayne, M.L., Soderman, D.D., Kwok, P.W., Sullivan, K.W., Palisi, T.M., Hope, D.A. and Thomas, K.A. (1990 a) Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 87:2628–2632.

    PubMed  CAS  Google Scholar 

  • Conn, G., Soderman, D.D., Schaeffer, M.-T, Wile, M., Hatcher, VB. and Thomas, K.A. (1990b) Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc. Natl. Acad. Sci. USA 87:1323–1327.

    PubMed  CAS  Google Scholar 

  • Connolly, D.T., Heuvelman, D.M., Nelson, R., Olander, J.V, Eppley, B.L., Delfino, J.J., Siegel, N.R., Leimgruber, R.M. and Feder, J. (1989a) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J. Clin. Invest. 84:1470–1478.

    PubMed  CAS  Google Scholar 

  • Connolly, D.T., Olander, J.V, Heuvelman, D., Nelson, R., Monsell, R., Siegel, N., Haymore, B.L., Leimgruber, R. and Feder, J. 1989b) Human vascular permeability factor. Isolation from U937 cells. J. Biol. Chem. 264:20017–20024.

    PubMed  CAS  Google Scholar 

  • Criscuolo, G.R. (1993) The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J. Biol. Med. 66: 277–314.

    PubMed  CAS  Google Scholar 

  • Cullinan-Bove, K. and Koos, R. (1993) Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: Rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133: 829–837.

    PubMed  CAS  Google Scholar 

  • D’Angelo, G., Struman, I., Martial, J. and Weiner, R.I. (1995) Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc. Natl. Acad. Sci. USA 92:6374–6378.

    PubMed  Google Scholar 

  • Danø, K., Andreasen, P.A., Grøndahl-Hansen, J., Kristensen, P., Nielsen, L.S. and Skriver, L. (1985) Plasminogen activators, tissue degradation, and cancer. Adv. Cancer Res. 44: 139–266.

    PubMed  Google Scholar 

  • de Vries, C., Escobedo, J.A., Ueno, H., Houck, K., Ferrara, N. and Williams, L.T. (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991.

    CAS  Google Scholar 

  • Derynck, R., Goeddel, D.V, Ullrich, A., Gutterman, J.U., Williams, R.D., Bringman, TS. And Berger, WH. (1987) Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 47:707–712.

    PubMed  CAS  Google Scholar 

  • Detmar, M., Brown, L., Claffey, K., Yeo, K.-T, Kocher, O., Jackman, R., Berse, B. and Dvorak, H. (1994) Overexpression of vascular permeability factor and its receptors in psoriasis. J. Exp. Med. 180:1141–1146.

    PubMed  CAS  Google Scholar 

  • Detmar, M., Brown, L., Dvorak, H. and Claffey, K. (1995 a) Overexpression of VPF/VEGF in the skin of transgenic mice leads to increased skin vascularization. J. Invest. Derm. 105:448 (abstract).

    Google Scholar 

  • Detmar, M., Yeo, K.T., Nagy, J.A., Van De Water, L., Brown, L.F., Berse, B., Elicker, B.M., Ledbetter, S. and Dvorak, H.F. (1995b) Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J. Invest. Dermatol. 105:44–50.

    PubMed  CAS  Google Scholar 

  • DiSalvo, J., Bayne, M.L., Conn, G., Kwok, P.W, Trivedi, P.G., Soderman, D.D., Palisi, T.M., Sullivan, K.A. and Thomas, K.A. (1995) Purification and characterization of a naturally occurring vascular endothelial growth factor placenta growth factor heterodimer. J. Biol. Chem. 270:7717–7723.

    PubMed  CAS  Google Scholar 

  • Dolecki, G.J. and Connolly, D.T. (1991) Effects of a variety of cytokines and inducing agents on vascular permeability factor mRNA levels in U937 cells. Biochem. Biophys. Res. Commun. 180:572–578.

    PubMed  CAS  Google Scholar 

  • Dougher-Vermazen, M., Hulmes, J.D., Bohlen, P. and Terman, B.I. (1994) Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor. Biochem. Biophys. Res. Commun. 205:728–738.

    PubMed  CAS  Google Scholar 

  • Drake, C. and Little, C. (1995) Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc. Natl. Acad. Sci. USA 92:7657–7661.

    PubMed  CAS  Google Scholar 

  • Dumont, D.J., Fong, G.H., Puri, M.C., Gradwohl, G., Alitalo, K. and Breitman, M.L. (1995) Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev. Dyn. 203:80–92.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.F. (1986) Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315:1650–1659.

    CAS  Google Scholar 

  • Dvorak, H.F, Dvorak, A.M., Manseau, E.J., Wiberg, L. and Churchill, WH. (1989a) Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J. Natl. Cancer Inst. 62:1459–1472.

    Google Scholar 

  • Dvorak, H.F., Orenstein, N.S., Carvalho, A.C., Churchill, W.H., Dvorak, A.M., Galli, S.J., Feder, J., Bitzer, A.M., Rypysc, J. and Giovinco, P. (1979 b) Induction of a fibrin-gel investment: An early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J. Immunol. 122:166–174.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.F, Quay, S.C., Orenstein, N.S., Dvorak, A.M., Hahn, P., Bitzer, A.M. and Carvalho, A.C. (1981) Tumor shedding and coagulation. Science 212:923–924.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.F, Senger, D.R. and Dvorak, A.M. (1983 a) Fibrin as a component of the tumor stroma: Origins and biological significance. Cancer Metastasis Rev. 2:41–73.

    PubMed  CAS  Google Scholar 

  • Dvorak H.F., Van De Water, L., Bitzer, A.M., Dvorak, A.M., Anderson, D., Harvey, VS., Bach, R., Davis, G.L., De Wolf, W and Carvalho, A.C.A. (1983 b) Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res. 43:4434–4442.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.K, Form, D.M., Manseau, E.J. and Smith, B.D. (1984a) Pathogenesis of desmoplasia. I. Immunofluorescence identification and localization of some structural proteins of line 1 and line 10 guinea pig tumors and of healing wounds. J. Natl. Cancer Inst. 73: 1195–1205.

    CAS  Google Scholar 

  • Dvorak, H.F, Harvey, VS. and McDonagh, J. (1984b) Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res. 44:3348–3354.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.F, Senger, D.R., Dvorak, A.M., Harvey, VS. and Donagh, J. (1985) Regulation of extravascular coagulation by microvascular permeability. Science 277:1059–1061.

    Google Scholar 

  • Dvorak, H.F, Harvey, VS., Estrella, P., Brown, L.F., McDonagh, J. and Dvorak, A.M. (1987) Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab. Invest. 57:673–686.

    CAS  Google Scholar 

  • Dvorak, H.F, Nagy, J.A., Dvorak, J.T. and Dvorak, A.M. (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am. J. Pathol. 133:95–109.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.F, Nagy, J.A. and Dvorak, A.M. (1991a) Structure of solid tumors and their vasculature: Implications for therapy with monoclonal antibodies. Cancer Cells 3:77–85.

    PubMed  CAS  Google Scholar 

  • Dvorak, H.F, Sioussat, T.M., Brown, L.F, Berse, B., Nagy, J.A., Sotrel, A., Manseau, E.J., Van De Water, L. and Senger, D.R. (1991 b) Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors. Concentration in tumor blood vessels. J. Exp. Med. 174:1275–1278.

    CAS  Google Scholar 

  • Dvorak, H.F., Brown, L.F, Detmar, M. and Dvorak, A.M. (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146:1029–1039.

    PubMed  CAS  Google Scholar 

  • Dvorak, A., Kohn, S., Morgan, E., Fox, P., Nagy, J. and Dvorak, H. (1996) The vesiculo-vacuolar organelle (WO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J. Leukocyte Biol. 59:100–115.

    PubMed  CAS  Google Scholar 

  • Eichmann, A., Marcelle, C, Breant, C. and Le Douarin, N.M. (1993) Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development. Mech. Dev. 42:33–48.

    PubMed  CAS  Google Scholar 

  • Fava, R., Olsen, N., Spencer-Green, G., Yeo, K.-T., Yeo, T.-K., Berse, B., Jackman, R., Senger, D., Dvorak, H. and Brown, L. (1994) Vascular permeability factor/endothelial growth factor (VPF/VEGF): Accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J. Exp. Med. 180:341–346.

    PubMed  CAS  Google Scholar 

  • Favard, C, Moukadiri, H., Dorey, C, Praloran, V. and Plouet, J. (1991) Purification and biological properties of vasculotropin, a new angiogenic cytokine. Biol. Cell 73:1–6.

    PubMed  CAS  Google Scholar 

  • Feng, D., Nagy, J., Hipp, J., Dvorak, H. and Dvorak, A. (1995) Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), vesiculo-vacuolar organelles (VVOs), and regulation of vascular permeability. Mol. Biol. Cell 6 (suppl):335a.

    Google Scholar 

  • Feng, D., Nagy, J. A., Hipp, J., Dvorak, H.F. and Dovorak, A.M. (1996) Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J. Exp. Med. 183:1981–1986.

    PubMed  CAS  Google Scholar 

  • Ferrara, N. and Henzel, W.J. (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161:851–858.

    PubMed  CAS  Google Scholar 

  • Ferrara, N., Winer, J., Burton, T, Rowland, A. Siegel, M., Phillips, H.S., Terrell, T., Keller, G.A. and Levinson, A.D. (1993) Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chines hamster ovary cells. J. Clin. Invest. 91:160–170.

    PubMed  CAS  Google Scholar 

  • Finkenzeller, G., Marme, D., Weich, H.A. and Hug, H. (1992) Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res. 52:4821–4823.

    PubMed  CAS  Google Scholar 

  • Finkenzeller, G., Technau, A., Marme, D. (1995) Hypoxia-induced transcription of the vascular endothelial growth factor gene is independent of functional AP-1 transcription factor. Biochem. Biophys. Res. Commun. 208:432–439.

    PubMed  CAS  Google Scholar 

  • Fischer, S., Sharma, H.S., Karliczek, G.F. and Schaper, W. (1995) Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine. Brain Res. Mol. Brain Res. 28:141–148.

    PubMed  CAS  Google Scholar 

  • Flamme, I., Breier, G. and Risau, W. (1995) Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo. Dev. Biol. 169:699–712.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Frank, S., Hubner, G., Breier, G., Longaker, M.T., Greenhalgh, D.G. and Werner, S. (1995) Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J. Biol. Chem. 270:12607–12613.

    CAS  Google Scholar 

  • Garrido, C., Saule, S. and Gospodarowicz, D. (1993) Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. Growth Factors 8:109–117.

    PubMed  CAS  Google Scholar 

  • Gengrinovitch, S., Greenberg, S.M., Cohen, T, Gitay, G.H., Rockwell, P., Maione, T.E., Levi, B.Z. and Neufeld, G. (1995) Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms. J. Biol. Chem. 270:15059–15065.

    PubMed  CAS  Google Scholar 

  • Gitay-Goren, H., Soker, S., Vlodavsky, I. and Neufeld, G. (1992) The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules. J. Biol. Chem. 267:6093–6098.

    PubMed  CAS  Google Scholar 

  • Gitay-Goren, H., Halaban, R. and Neufeld, G. (1993) Human melanoma cells but not normal melanocytes express vascular endothelial growth factor receptors. Biochem. Biophys. Res. Commun. 190:702–709.

    PubMed  CAS  Google Scholar 

  • Goldberg, M. and Schneider, T. (1994) Similarities between the oxygen sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J. Biol. Chem. 269:4355–4359.

    PubMed  CAS  Google Scholar 

  • Gospodarowicz, D., Abraham, J.A. and Schilling, J. (1989) Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc. Natl. Acad. Sci. USA. 86:7311–7315.

    PubMed  CAS  Google Scholar 

  • Goto, F., Goto, K., Weindel, K. and Folkman, J. (1993) Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab. Invest. 69:508–517.

    PubMed  CAS  Google Scholar 

  • Green, L., Jellinek, D., Bell, C, Beebe, L., Feistner, B., Gill, S., Jucker, F. and Janjic, N. (1995) Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor. Chemistry & Biology 2:683–695.

    CAS  Google Scholar 

  • Grugel, S., Finkenzeller, G., Weindel, K., Barleon, B., Marme, D. (1995) Both v-Ha-ras and v-raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J. Biol. Chem. 270:25915–25919.

    PubMed  CAS  Google Scholar 

  • Guerrin, M., Moukadiri, H., Chollet, P., Moro, F., Dutt, K., Malacaze, F. and Plouet, J. (1995) Vasculotropin/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro. J. Cell Physiol. 164:385–394.

    PubMed  CAS  Google Scholar 

  • Guidi, A., Abu-Jawdeh, G., Berse, B., Jackman, R., Tognazzi, K., Dvorak, H. and Brown, L. (1995) Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J. Natl. Cancer Institute 87:1237–1245.

    CAS  Google Scholar 

  • Guo, D., Jia, Q., Song, H.Y., Warren, R.S. and Donner, D.B. (1995) Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J. Biol. Chem. 270:6729–6733.

    CAS  Google Scholar 

  • Haddow, A. (1972) Molecular repair, wound healing, and carcinogenesis: Tumor production a possible overhealing? Adv. Cancer Res. 16:181–234.

    PubMed  CAS  Google Scholar 

  • Harada, S., Nagy, J.A., Sullivan, K.A., Thomas, K.A., Endo, N., Rodan, G.A. and Rodan, S.B. (1994) Induction of vascular endothelial growth factor expression by prostaglandin E2 and El in osteoblasts. J. Clin. Invest. 93:2490–2496.

    PubMed  CAS  Google Scholar 

  • Harrison-Woolrych, M., Sharkey, A.M., Charnock, J.D. and Smith, S.K. (1995) Localization and quantification of vascular endothelial growth factor messenger ribonucleic acid in human myometrium and leiomyomata. J. Clin. Endocrinol. Metab. 80:1853–1858.

    PubMed  CAS  Google Scholar 

  • Hashimoto, E., Kage, K., Ogita, T., Nakaoka, T, Matsuoka, R. and Kira, Y. (1994a) Adenosine as an endogenous mediator of hypoxia for induction of vascular endothelial growth factor mRNA in U-937 cells. Biochem. Biophys. Res. Commun. 204:318–324.

    PubMed  CAS  Google Scholar 

  • Hashimoto, E., Ogita, T, Nakaoka, T, Matsuoka, R., Takao, A. and Kira, Y. (1994b) Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am. J. Physiol. 267:1948–1954.

    Google Scholar 

  • Hata, Y., Nakagawa, K., Ishibashi, T., Inomata, H., Ueno, H. and Sueishi, K. (1995) Hypoxia-induced expression of vascular endothelial growth factor by retinal glial cells promotes in vitro angiogenesis. Virchows Arch. 426:479–486.

    PubMed  CAS  Google Scholar 

  • Hatva, E., Kaipainen, A., MĂ©ntula, P., Jaaskelainen, J., Paetau, A., Haltia, M. and Alitalo, K. (1995) Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am. J. Pathol. 146:368–378.

    PubMed  CAS  Google Scholar 

  • Heslan, J.M., Branellec, A.I., Pilatte, Y, Lang, P. and Lagrue, G. (1991) Differentiation between vascular permeability factor and IL-2 in lymphocyte supernatants from patients with minimal-change nephrotic syndrome. Clin. Exp. Immunol. 86:157–162.

    PubMed  CAS  Google Scholar 

  • Hlatky, L., Tsionou, C., Hahnfeldt, P. and Coleman, C.N. (1994) Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54:6083–6086.

    PubMed  CAS  Google Scholar 

  • Hom, D.B. and Assefa, G. (1992) Effects of endothelial cell growth factor on vascular compromised skin flaps. Arch. Otolaryngol. Head Neck Surg. 118:624–628.

    PubMed  CAS  Google Scholar 

  • Houck, K.A., Ferrara, N., Winer, J., Cachianes, G., Li, B. and Leung, D.W. (1991) The vascular endothelial growth factor family: Identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol 5:1806–1814.

    PubMed  CAS  Google Scholar 

  • Houck, K.A., Leung, D.W., Rowland, A.M., Winer, J. and Ferrara, N. (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem. 267:26031–26037.

    PubMed  CAS  Google Scholar 

  • Iizuka, M., Yamauchi, M., Ando, K., Hori, N., Furusawa, Y, Itsukaichi, H., Fukutsu, K. and Moriya, H. (1994) Quantitative RT-PCR assay detecting the transcriptional induction of vascular endothelial growth factor under hypoxia. Biochem. Biophys. Res. Commun. 205: 1474–1480.

    PubMed  CAS  Google Scholar 

  • Jackson, M.R., Carney, E.W., Lye, S.J. and Ritchie, J.W. (1994) Localization of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta 15:341–353.

    PubMed  CAS  Google Scholar 

  • Jakeman, L., Winer, J., Bennett, G., Altar, C, and Ferrara, N. (1992) Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J. Clin. Invest. 89:244–253.

    PubMed  CAS  Google Scholar 

  • Jakeman, L.B., Armanini, M., Phillips, H.S. and Ferrara, N. (1993) Developmental expression of binding sites and messenger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology 133:848–859.

    PubMed  CAS  Google Scholar 

  • Karnat, B.R., Brown, L.F, Manseau, E.J., Senger, D.R. and Dvorak, H.F. (1995) Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells: Role in corpus luteum development. Am. J. Pathol. 146:157–165.

    Google Scholar 

  • Keck, P.J., Hauser, S.D., Krivi, G., Sanzo, K., Warren, T, Feder, J. and Connolly, D.T. (1989) Vascular permeability factor, and endothelial cell mitogen related to PDGF. Science 246:1309–1312.

    PubMed  CAS  Google Scholar 

  • Kieser, A., Weich, H., Brandner, G., Marme, D. and Kolch, W. (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969.

    PubMed  CAS  Google Scholar 

  • Kim, J., Li, B., Weiner, J., Houck, K. and Ferrara, N. (1992). The vascular endothelial cell growth factor family. Identification of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors 7:53–64.

    CAS  Google Scholar 

  • Koch, A.E., Harlow, L.A., Haines, G.K., Amento, E.P., Unemori, E.N., Wong, W.L., Pope, R.M. and Ferrara, N. (1994) Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J. Immunol. 152:4149–4156.

    CAS  Google Scholar 

  • Kohn, S., Nagy, J.A., Dvorak, H.F. and Dvorak, A.M. (1992) Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab. Invest. 67:596–607.

    CAS  Google Scholar 

  • Kondo, S., Asano, M. and Suzuki, H. (1993) Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody. Biochem. Biophys. Res. Commun. 194:1234–1241.

    PubMed  CAS  Google Scholar 

  • Kondo, S., Asano, M., Matsuo, K., Ohmori, I. and Suzuki, H. (1994) Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim. Biophys. Acta 1221:211–214.

    PubMed  CAS  Google Scholar 

  • Koos, R.D. and Olson, CE. (1991) Hypoxia stimulates expression of the gene for vascular endothelial growth factor (VEGF), a putative angiogenic factor, by granulosa cells of the ovarian follicle, a site of angiogenesis. J. Cell Biol. 115:421 A.

    Google Scholar 

  • Koos, R. (1995) Increased expression of vascular endothelial growth/permeability factor in the rat ovary following an ovulatory gonadotropin stimulus: potential roles in follicle rupture. Biology of Reproduction 52:1426–1435.

    PubMed  CAS  Google Scholar 

  • Ku, D.D., Zaleski, J.K., Liu, S. and Brock, T.A. (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am. J. Physiol. 265:h586–592.

    PubMed  CAS  Google Scholar 

  • Kuroda, M., Oka, T., Oka, Y., Yamochi, T., Ohtsubo, K., Mori, S., Watanabe, T., Machinami, R. and Ohnishi, S. (1995) Colocalization of vascular endothelial growth factor (vascular permeability factor) and insulin in pancreatic islets. Journal of Endocrinology and Metabolism 80:3196–3200.

    CAS  Google Scholar 

  • Ladoux, A. and Frelin, C. (1993) Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem. Biophys. Res. Commun. 195 (2): 1005–1010.

    PubMed  CAS  Google Scholar 

  • Ladoux, A. and Frelin, C. (1994) Cobalt stimulates the expression of vascular endothelial growth factor mRNA in rat cardiac cells. Biochem. Biophys. Res. Commun. 204:794–798.

    PubMed  CAS  Google Scholar 

  • Lanir, N., Ciano, P.S., Van De Water, L., McDonagh, J., Dvorak, A.M. and Dvorak, H.F. (1988) Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration. J. Immunol. 140:2340–2349.

    PubMed  CAS  Google Scholar 

  • Leung, D.W., Cachianes, G., Kuang, W.-J., Goeddel, D.V, Ferrara, N. (1989) Vascular endothelial growth factor is secreted angiogenic mitogen. Science 246:1306–1309.

    PubMed  CAS  Google Scholar 

  • Levy, A.P., Levy, N.S., Loscalzo, J., Calderone, A., Takahashi, N., Yeo, K.T., Koren, G., Colucci, WS. and Goldberg, M.A. (1995 a) Regulation of vascular endothelial growth factor in cardiac myocytes. Circ. Res. 76:758–766.

    PubMed  CAS  Google Scholar 

  • Levy, A.P., Levy, N.S., Wegner, S. and Goldberg, M.A. (1995 b) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J. Biol. Chem. 270:13333–13340.

    PubMed  CAS  Google Scholar 

  • Li, X.F., Gregory, J. and Ahmed, A. (1994) Immunolocalisation of vascular endothelial growth factor in human endometrium. Growth Factors 11:277–282.

    PubMed  CAS  Google Scholar 

  • Li, J., Perrella, M.A., Tsai, J.C, Yet, S.F., Hsieh, CM., Yoshizumi, M., Patterson, C, Endege, W.O., Zhou, F. and Lee, M.E. (1995) Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J. Biol. Chem. 270:308–312.

    PubMed  CAS  Google Scholar 

  • Li, J, Brown, L., Hibberd, M., Grossman, J., Morgan, J. and Simons, M. (1996). VEGF, Flk-1 and Flt-1 expression in a rat myocardial infarction model of angiogenesis. Am. J. Physiol. 270:H 1803–H 1811.

    Google Scholar 

  • Liu, Y, Cox, S.R., Morita, T. and Kourembanas, S. (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ. Res. 77:638–643.

    PubMed  CAS  Google Scholar 

  • Lyttle, D.J., Fraser, K.M., Fleming, S.B., Mercer, A.A. and Robinson, A.J. (1994) Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus. J. Virol. 68: 84–92.

    PubMed  CAS  Google Scholar 

  • Maglione, D., Guerriero, V, Viglietto, G., Delli-Bovi, P. and Persico, M.G. (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl. Acad. Sci. USA 88:9267–9271.

    PubMed  CAS  Google Scholar 

  • Mandriota, S.J., Seghezzi, G., Vassalli, J.D., Ferrara, N., Wasi, S., Mazzieri, R., Mignatti, P. and Pepper, M.S. (1995) Vascular endothelial growth factor increases urokinase receptor expres¬sion in vascular endothelial cells. J. Biol. Chem. 270:9709–9716.

    PubMed  CAS  Google Scholar 

  • Maruyama, K., Tomizawa, S., Seki, Y, Arai, H., Ogawa, T. and Kuroume, T. (1994) FK 506 for vascular permeability factor production in minimal change nephrotic syndrome [letter]. Nephron. 66:486–487.

    PubMed  CAS  Google Scholar 

  • Matthews, W, Jordan, C, Gavin, M., Jenkins, N., Copeland, N. and Lemischka, I. (1991) A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hemato-poietic cells and exhibiting close genetic linkage to c-kit. Proc. Natl. Acad. Sci. USA 88:9026–9030.

    PubMed  CAS  Google Scholar 

  • McClure, N., Healy, D.L., Rogers, P.A., Sullivan, J., Beaton, L., Haning, R.J., Connolly, D.T. and Robertson, D.M. (1994) Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 344:235–236.

    PubMed  CAS  Google Scholar 

  • Midy, V and Plouet, J. (1994) Vasculotropin/Vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem. Biophys. Res. Commun. 199:380–386.

    PubMed  CAS  Google Scholar 

  • Millauer, B., Wizigmann-Voos, S., Schnurch, H., Martinez, R., Moller, N., Risau, W. and Ullrich, A. (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846.

    PubMed  CAS  Google Scholar 

  • Millauer, B., Shawver, L., Plate, K., Risau, W., Ullrich, A. (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579.

    PubMed  CAS  Google Scholar 

  • Miller, J.W., Adamis, A.P., Shima, D.T., D’Amore, P.A., Moulton, R.S., O’Reilly, M.S., Folkman, J., Dvorak, H.F, Brown, L.F., Berse, B. Yeo, T.-K. and Yeo, K.-T. (1994) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am. J. Pathol. 145:574–584.

    PubMed  CAS  Google Scholar 

  • Minchenko, A., Bauer, T., Salceda, S. and Caro, J. (1994a) Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab. invest. 71:374–379.

    PubMed  CAS  Google Scholar 

  • Minchenko, A., Salceda, S., Bauer, T. and Caro, J. (1994b) Hypoxia regulatory elements of the human vascular endothelial growth factor gene. Cell. Mol. Biol. Res. 40:35–39.

    PubMed  CAS  Google Scholar 

  • Monacci, W.T., Merrill, M.J. and Oldfield, E.H. (1993) Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am. J. Physiol. 264: c995–cl002.

    Google Scholar 

  • Morii, K., Tanaka, R., Washiyama, K., Kumanishi, T. and Kuwano, R. (1993) Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem. Biophys. Res. Commun. 194:749–755.

    PubMed  CAS  Google Scholar 

  • Mukhopadhyay, D., Tsiokas, L., Zhou, X.M., Foster, D., Brugge, J.S. and Sukhatme, VP. (1995) Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375:577–581.

    PubMed  CAS  Google Scholar 

  • Murata, T., Ishibashi, T., Khalil, A., Hata, Y, Yoshikawa, H. and Inomata, H. (1995) Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels.Ophthalmic Research 27:48–52.

    PubMed  CAS  Google Scholar 

  • Mustonen, T. and Alitalo, K. (1995) Endothelial receptor tyrosine kinases involved in angiogenesis. J. Cell. Biol. 129:895–898.

    PubMed  CAS  Google Scholar 

  • Myoken, Y, Kayada, Y, Okamoto, T, Kan, M., Sato, G.H. and Sato, J.D. (1991) Vascular endothelial cell growth factor (VEGE) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites. Proc. Natl. Acad. Sci. USA 88:5819–5823.

    PubMed  CAS  Google Scholar 

  • Nagy, J.A., Herzberg, K.T., Masse, E.M., Zientara, G.P. and Dvorak, H.F. (1989) Exchange of macromolecules between plasma and peritoneal cavity in ascites tumor-bearing, normal, and serotonin-injected mice. Cancer Res. 49:5448–5458.

    PubMed  CAS  Google Scholar 

  • Nagy, J.A., Masse, E.M., Harvey-Bliss, VS., Meyers, M.S., Sioussat, T.M., Senger, D.R. and Dvorak, H.F. (1991) Immunochemical localization of vascular permeability factor (vascular endothelial growth factor) in ascites tumors: Distribution in peritoneal wall microvasculature. J. Cell. Biol. 115:264 a.

    Google Scholar 

  • Nagy, J.A., Herzberg, K.T., Dvorak J.M. and Dvorak, H.F. (1993) Pathogenesis of malignant ascites formation: Initiating events that lead to fluid accumulation. Cancer Res. 2631–2643.

    Google Scholar 

  • Nagy, J., Morgan, E., Herzberg, K., Manseau, E., Dvorak, A. and Dvorak, H. (1995 a) Pathogenesis of ascites tumor growth. Angiogenesis, vascular remodeling and stroma formation in the peritoneal lining. Cancer Res. 55:376–385.

    PubMed  CAS  Google Scholar 

  • Nagy, J.A., Masse, E.M., Herzberg, K.T., Meyers, M.S., Yeo, K.-T., Yeo, T.-K., Sioussat, T.M. and Dvorak, H.F. (1995 b) Pathogenesis of ascites tumor growth. Vascular permeability factor, vascular hyperpermeability and ascites fluid accumulation. Cancer Res. 55:360–368.

    PubMed  CAS  Google Scholar 

  • Nagy, J.A., Meyers, M.S., Masse, E.M., Herzberg, K.T. and Dvorak, H.F. (1995 c) Pathogenesis of ascites tumor growth. Fibrinogen influx and fibrin accumulation in tissues lining the peritoneal cavity. Cancer Res. 55:369–375.

    CAS  Google Scholar 

  • Olander, J.V, Connolly, D.T. and DeLarco, J.E. (1991) Specific binding of vascular permeability factor to endothelial cells. Biochem. Biophys. Res. Commun. 175:68–76.

    PubMed  CAS  Google Scholar 

  • Olson, T.A., Mohanraj, D., Carson, L.F. and Ramakrishnan, S. (1994) Vascular permeability factor gene expression in normal and neoplastic human ovaries. Cancer Res. 54:276–280.

    PubMed  CAS  Google Scholar 

  • Palade, G.E. (1988) The microvascular endothelium revisited. In: N. Simionescu and M. Simionescu (eds): Endothelial Cell Biology in Health and Disease. Plenum Press, New York, pp 3–22.

    Google Scholar 

  • Park, J., Keller, G.-A. and Ferrara, N. (1993) The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol Cell 4:1317–1326.

    PubMed  CAS  Google Scholar 

  • Park, IE., Chen, H.H., Winer, J., Houck, K.A., Ferrara, N. (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-l/KDR. J. Biol Chem. 269:25646–25654.

    CAS  Google Scholar 

  • Pe’er, J., Shweiki, D., Itin, A., Hemo, I., Gnessin, H. and Keshet, E. (1995) Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab. Invest. 72:638–645.

    PubMed  Google Scholar 

  • Pekala, P., Marlow, M., Heuvelman, D. and Connolly D. (1990) Regulation of hexose transport in aortic endothelial cells by vascular permeability factor and tumor necrosis factor-alpha, but not by insulin. J. Biol. Chem. 265:18051–18054.

    PubMed  CAS  Google Scholar 

  • Pepper, M.S., Ferrara, N., Orci, L. and Montesano, R. (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem. Biophys. Res. Commun. 181:902–906.

    PubMed  CAS  Google Scholar 

  • Pepper, M.S., Ferrara, N., Orci, L. and Montesano, R. (1992) Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem. Biophys. Res. Commun. 189:824–831.

    PubMed  CAS  Google Scholar 

  • Peretz, D., Gitay-Goren, M., Safran, M., Kimmel, N., Gospodarowicz, D. and Neufeld, G. (1992) Glycosylation of vascular endothelial growth factor is not required for its mitogenic activity. Biochem. Biophys. Res. Commun. 1882:1340–1347.

    Google Scholar 

  • Pertovaara, L., Kaipainen, A., Mustonen, T., Orpana, A., Ferrara, N., Saksela, O. and Alitalo, K. (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-$b in fibroblastic and epithelial cells. J. Biol Chem. 269:6271–6274.

    PubMed  CAS  Google Scholar 

  • Peters, K., DeVries, C, Williams, L. (1993) Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc. Natl Acad. Sci. 90:8915–8919.

    PubMed  CAS  Google Scholar 

  • Phillips, H.S., Hains, J., Leung, D.W. and Ferrara, N. (1990) Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology 127: 965–967.

    PubMed  CAS  Google Scholar 

  • Phillips, G.D., Stone, A.M., Jones, B.D., Schultz, J.C, Whitehead, R.A. and Knighton, D.R. (1994) Vascular endothelial growth factor (rhVEGF165) stimulates direct angiogenesis in the rabbit cornea. In Vivo 8:961–965.

    PubMed  CAS  Google Scholar 

  • Pierce, E.A., Avery, R.L., Foley, E.D., Aiello, L.P. and Smith, L.E. (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc. Natl. Acad. Sci. USA 92:905–909.

    PubMed  CAS  Google Scholar 

  • Plate, K.H., Breier, G., Weich, H.A. and Risau, W. (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848.

    PubMed  CAS  Google Scholar 

  • Plate, K.H., Breier, G., Millauer, B., Ullrich, A. and Risau, W. (1993) Up-regulation of vascular endothelial growth factor and its cognate receptors in an rat glioma model of tumor angiogenesis. Cancer Res. 53:5822–5827.

    PubMed  CAS  Google Scholar 

  • Plate, K.H., Breier, G., Weich, H.A., Mennel, H.D. and Risau, W. (1994) Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGE protein and possible in vivo regulatory mechanisms. Int. J. Cancer 59:520–529.

    PubMed  CAS  Google Scholar 

  • Potgens, A.J., Lubsen, N.H., Vermeulen, R. van, Bakker, A., Schoenmakers, J.G., Ruiter, D.J. and de Waal, R. (1994) Covalent dimerization of vascular permeability factor/vascular endothelial growth factor is essential for its biological activity. Evidence from Cys to Ser mutations. J. Biol. Chem. 269:32879–32885.

    CAS  Google Scholar 

  • Praloran, V, Mirshahi, S., Favard, C, Moukadiri, H. and Plouet, J. (1991) Vasculotropin is mitogenic for human peripheral lymphocytes. C. R. Acad. Sci. Paris 313 111:21–26.

    PubMed  CAS  Google Scholar 

  • Qu-Hong, Nagy, J.A., Senger, D.R., Dvorak, H.F. and Dvorak, A.M. (1995) Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the abluminal plasma membrane and vesicuolo-vacuolar organelles of tumor microvascular endothelium. J. Histochem. Cytochem. 43:381–389.

    PubMed  CAS  Google Scholar 

  • Quinn, T., Peters, K., DeVries, C, Ferrara, N. and Williams, L. (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc. Natl. Acad. Sci. USA 90:7533–7537.

    PubMed  CAS  Google Scholar 

  • Rak, J., Filmus, J., Finkenzeller, G., Grugel, S., Marme, D. and Kerbel, R. (1995 a) Oncogenes as inducers of tumor angiogenesis. Cancer and Metastasis Research 14:263–277.

    CAS  Google Scholar 

  • Rak, J., Mitsuhashi, Y., Bayko, L., Filmus, J., Shirasawa, S., Sasazuki, T. and Kerbel, R. (1995b) Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55:4575–4580.

    PubMed  CAS  Google Scholar 

  • Ravindranath, N., Little-Ihrig, L., Phillips, H.S., Ferrara, N. and Zeleznik, A.J. (1992) Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology 131:254–260.

    PubMed  CAS  Google Scholar 

  • Roberts, W. and Palade, G. (1995) Increased microvasculatur permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Science 108:2369–2379.

    PubMed  CAS  Google Scholar 

  • Samoto, K., Ikezaki, K., Ono, M., Shono, T., Kohno, K., Kuwano, M. and Fukui, M. (1995) Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res. 55:1189–1193.

    PubMed  CAS  Google Scholar 

  • Sato, K., Terada, K., Sugiyama, T., Takahashi, S., Saito, M., Moriyama, M., Kakinuma, H., Suzuki, Y, Kato, M. and Kato, T. (1994) Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. Tohoku J. Exp. Med. 173:355–360.

    PubMed  CAS  Google Scholar 

  • Sato, K., Yamazaki, K., Shizume, K., Kanaji, Y, Obara, T, Ohsumi, K., Demura, H., Yamaguchi, S. and Shibuya, M. (1995) Stimulation by thyroid-stimulating hormone and Graves’ immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo. J. Clin. Invest. 96: 1295–1302.

    PubMed  CAS  Google Scholar 

  • Seetharam, L., Gotoh, N., Mam, Y, Neufeld, G., Yamaguchi, S. and Shibuya, M. (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF.Oncogene 10:135–147.

    PubMed  CAS  Google Scholar 

  • Senger, D.R. and Dvorak, H.F. (1993) Vascular permeability factor in astrocytomas and other tumors. In: P.M. Black and L. Lampson (eds): Astrocytomas: Diagnosis, Treatment, and Biology. Blackwell Scientific Publications, London, pp 250–260.

    Google Scholar 

  • Senger, D.R., Galli, S.J., Dvorak, A.M., Perruzzi, C.A., Harvey, VS. and Dvorak, H.F. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985.

    PubMed  CAS  Google Scholar 

  • Senger, D.R., Perruzzi, C.A., Feder, J. and Dvorak, H.F. (1986) A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 46:5629–5632.

    PubMed  CAS  Google Scholar 

  • Senger, D.R., Connolly, D.T, Van De Water, L., Feder, J. and Dvorak, H.F. (1990) Purification and NH2-terminal amino acid sequence off guinea pig tumor-secreted vascular permeability factor. Cancer Res. 50:1774–1778.

    PubMed  CAS  Google Scholar 

  • Senger, D., Van De Water, L., Brown, L., Nagy, J., Yeo, K.-T, Yeo, T.-K., Berse, B., Jackman, R., Dvorak, A. and Dvorak, H. (1993) Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev. 12:303–324.

    PubMed  CAS  Google Scholar 

  • Shalaby, F., Rossant, J., Yamaguchi, T.P., Gertsenstein, M., Wu, X.F., Breitman, M.L. and Schuh, A.C. (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66.

    PubMed  CAS  Google Scholar 

  • Sharkey, A., Charnock-Jones, Boocock, C, Brown, K. and Smith, S. (1993) Expression of mRNA for vascular endothelial growth factor in human placenta. J. Reproduction and Fertility 99:609–615.

    CAS  Google Scholar 

  • Shen, H., Clauss, M., Ryan, J., Schmidt, A.M., Tijburg, P., Borden, L., Connolly, D., Stern, D. and Kao, J. (1993) Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood 81:2767–2773.

    PubMed  CAS  Google Scholar 

  • Shifren, J.L., Doldi, N., Ferrara, N., Mesiano, S. and Jaffe, R.B. (1994) In the human fetus, vascular endothelial growth factor is expressed in epithelial cells and myocytes, but not vascular endothelium: implications for mode of action. J. Clin. Endocrinol. Metab. 79: 316–322.

    PubMed  CAS  Google Scholar 

  • Shweiki, D., Itin, A., Soffer D. and Keshet, E. (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845.

    PubMed  CAS  Google Scholar 

  • Shweiki, D., Itin, A., Neufeld, G., Gitay, G.H. and Keshet, E. (1993) Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J. Clin. Invest. 91:2235–2243.

    PubMed  CAS  Google Scholar 

  • Shweiki, D., Neeman, M., Itin, A. and Keshet, E. (1995) Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multiceli spheroids: implications for tumor angiogenesis. Proc. Natl. Acad. Sci. USA 92:768–772.

    PubMed  CAS  Google Scholar 

  • Simon, M., Grone, HJ., Johren, O., Kullmer, J., Plate, K.H., Risau, W. and Fuchs, E. (1995) Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am. J. Physiol. 268: f240–250.

    PubMed  CAS  Google Scholar 

  • Sioussat, T.M., Dvorak, H.F, Brock, T.A. and Senger, D.R. (1993) Inhibition of vascular permeability factor (vascular endothelial growth factor) with anti-peptide antibodies. Arch. Biochem. Biophys. 301:15–20.

    PubMed  CAS  Google Scholar 

  • Soker, S., Svahn, CM. and Neufeld, G. (1993) Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin. J. Biol. Chem. 268:7685–7691.

    PubMed  CAS  Google Scholar 

  • Stavri, G.T., Hong, Y., Zachary, I.C, Breier, G., Baskerville, P.A., Yla, H.S., Risau, W., Martin, J.F. and Erusalimsky, J.D. (1995 a) Hypoxia and platelet-derived growth factor-BB synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells. FEBS Lett 358:311–315.

    PubMed  CAS  Google Scholar 

  • Stavri, G.T., Zachary, I.C., Baskerville, P.A., Martin, J.F. and Erusalimsky, J.D. (1995b) Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. Circulation 92:11–14.

    CAS  Google Scholar 

  • Stepnick, D.W., Peterson, M.K., Bodgan, C., Davis, J., Wasman, J. and Mailer, K. (1995) Effects of tumor necrosis factor alpha and vascular permeability factor on neovascularization of the rabbit ear flap. Arch. Otolaryngol. Head Neck Surg 121:667–672.

    PubMed  CAS  Google Scholar 

  • Strugar, J., Rothbart, D., Harrington, W. and Criscuolo, G.R. (1994) Vascular permeability factor in brain metastases: correlation with vasogenic brain edema and tumor angiogenesis. J. Neurosurg. 81:560–566.

    PubMed  CAS  Google Scholar 

  • Sugihara, T., Kaul, S.C, Mitsui, Y. and Wadhwa, R. (1994) Enhanced expression of multiple forms of VEGF is associated with spontaneous immortalization of murine fibroblasts. Biochim. Biophys. Acta 1224:365–370.

    PubMed  Google Scholar 

  • Takahashi, A., Sasaki, H., Kim, S.J., Tobisu, K., Kakizoe, T., Tsukamoto, T., Kumamoto, Y, Sugimura, T. and Terada, M. (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 54:4233–4237.

    PubMed  CAS  Google Scholar 

  • Takashita, S., Pu, L.Q., Stein, L.A., Sniderman, A.D., Bunting, S., Ferrara, N., Isner, J.M. and Symes, J.F. (1994 a) Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation 90:1228–1234.

    Google Scholar 

  • Takeshita, S., Zheng, L.P, Brogi, E., Kearney, M., Pu, L.Q., Bunting, S., Ferrara, N., Symes, J.F. and Isner, J.M. (1994b) Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.J. Clin. Invest. 93:662–670.

    CAS  Google Scholar 

  • Terman, B.I., Carrion, M.E., Kovacs, E., Rasmussen, B.A., Eddy, R.L. and Shows, T.B. (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6:1677–1683.

    PubMed  CAS  Google Scholar 

  • Terman, B.I., Dougher-Vermazen, M., Carrion, M.E., Dimitrov, D., Armellino, D.C, Gospodarowicz, D. and Böhlen, P. (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun. 187:1579–1586.

    PubMed  CAS  Google Scholar 

  • Thieme, H., Aiello, L.P, Takagi, H., Ferrara, N. and King, G.L. (1995) Comparative analysis of vascular endothelial growth factor receptors on retinal and aortic vascular endothelial cells. Diabetes 44:98–103.

    PubMed  CAS  Google Scholar 

  • Tischer, E., Mitchell, R., Hartman, T, Silva, M., Gospodarowicz, D., Fiddes, J.D. and Abraham, J.A. (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266:11947–11954.

    CAS  Google Scholar 

  • Toi, M., Hoshina, S., Takayanagi, T. and Tominaga, T. (1994) Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn. J. Cancer Res. 85:1045–1049.

    PubMed  CAS  Google Scholar 

  • Tomizawa, S., Nagasawa, N., Maruyama, K., Shimabukuro, N., Arai, H. and Kuroume, T. (1990) Release of the vascular permeability factor in minimal change nephrotic syndrome is related to CD4+ lymphocytes [letter]. Nephron. 56:341–342.

    PubMed  CAS  Google Scholar 

  • Tuder, R.M., Flook, B.E. and Voelkel, N.F. (1995) Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Fit in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J. Clin. Invest. 95:1798–1807.

    CAS  Google Scholar 

  • Unemori, E.N., Ferrara, N., Bauer, E.A. and Amento, E.P. (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J. Cell. Physiol. 153:557–562.

    PubMed  CAS  Google Scholar 

  • Vaisman, N., Gospodarowicz, D. and Neufeld, G. (1990) Characterization of the receptors for vascular endothelial growth factor. J. Biol. Chem. 265:19461–19466.

    PubMed  CAS  Google Scholar 

  • Vinores, S., Kuchle, M., Mahlow, J., ChiĂą, C, Green, W. and Campochiaro, P. (1995) Blood-ocular barrier breakdown in eyes with ocular melanoma. A potential role for vascular endothelial growth factor/vascular permeability factor. Am. J. Pathol. 147:1289–1297.

    CAS  Google Scholar 

  • Waltenberger, J., Claesson, W.L., Siegbahn, A., Shibuya, M. and Heldin, C.H. (1994) Different signal transduction properties of KDR and Flt 1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269: 26988–26995.

    PubMed  CAS  Google Scholar 

  • Weindel, K., MarmĂ©, D. and Weich, H.A. (1992) AIDS-associated Kaposi’s sarcoma cells in culture express vascular endothelial growth factor. Biochem. Biophys. Res. Commun. 183:1167–1174.

    PubMed  CAS  Google Scholar 

  • Weindel, K., Moringlane, J.R., MarmĂ©, D. and Weich, H.A. (1994) Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? Neurosurgery 35:439–448.

    PubMed  CAS  Google Scholar 

  • Williams, B., Baker, A.Q., Gallacher, B. and Lodwick, D. (1995 a) Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension 25:913–917.

    PubMed  CAS  Google Scholar 

  • Williams, B., Quinn, B.A. and Gallacher, B. (1995 b) Serum and platelet-derived growth factor-induced expression of vascular permeability factor mRNA by human vascular smooth muscle cells in vitros. Clin. Sci. (Colch) 88:141–147.

    CAS  Google Scholar 

  • Wilting, J., Christ, B. and Weich, H.A. (1992) The effects of growth factors on the day 13 chorioallentoic membrane (CAM): A study of VEGF165 and PDGF-BB. Anatomy and Embryology 186:251–257.

    PubMed  CAS  Google Scholar 

  • Wizigmann-Voos, S., Breier, G., Risau, W. and Plate, K.H. (19995) Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 55:1358–1364.

    Google Scholar 

  • Yeo, T.-K. and Dvorak, H.F. (1995) Tumor stroma In: Colvin, R., Bhan, A. and McCluskey, R. (eds): Diagnostic Immunopathology 2, Raven Press, New York, pp 685–697.

    Google Scholar 

  • Yeo, T.-K., Brown, L. and Dvorak, H.F. (1991 a) Alterations in proteoglycan synthesis common to healing wounds and tumors. Am. J. Pathol. 138:1437–1450.

    PubMed  CAS  Google Scholar 

  • Yeo, T.-K., Senger, D.R., Dvorak, H.F, Freier, L. and Yeo, K.-T. (1991 b) Glycosylation is essential for efficient secretion but not for permeability-enhancing activity of vascular permeability factor (vascular endothelial growth factor). Biochem. Biophys. Res. Commun. 179:1568–1575.

    PubMed  CAS  Google Scholar 

  • Yeo, K.-T., Wang, H.H., Nagy, J.A., Sioussat, T.M., Ledbetter, S.R., Hoogewerf, A.J., Zhou, Y, Masse, E.M., Senger, D.R., Dvorak, H.F. and Yeo, T.-K. (1993) Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res. 53:2912–2918.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Pathology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts, 02159, USA

    L. F. Brown, M. Detmar, K. Claffey, J. A. Nagy, D. Feng, A. M. Dvorak & H. F. Dvorak

Authors
  1. L. F. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Detmar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Claffey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. A. Nagy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. M. Dvorak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. F. Dvorak
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Radiation Oncology, Long Island Jewish Medical Center, 270-05 76th Avenue New Hyde Park, 11042, New York, NY, USA

    Itzhak D. Goldberg M.D.  & Eliot M. Rosen M.D. Ph.D.  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1997 Birkhäuser Verlag Basel, Switzerland

About this chapter

Cite this chapter

Brown, L.F. et al. (1997). Vascular permeability factor/vascular endothelial growth factor:A multifunctional angiogenic cytokine. In: Goldberg, I.D., Rosen, E.M. (eds) Regulation of Angiogenesis. Experientia Supplementum, vol 79. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-9006-9_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-9006-9_10

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-9864-5

  • Online ISBN: 978-3-0348-9006-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation