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Vascular Growth Factors and Angiogenesis pp 97–132Cite as

Vascular Permeability Factor/Vascular Endothelial Growth Factor and the Significance of Microvascular Hyperpermeability in Angiogenesis

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 237))

Abstract

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) was originally discovered in the late 1970s because of its capacity to increase the permeability of microvessels to plasma and plasma proteins (Dvorak et al. 1979a,b). Using plastic-embedded, light microscopic section and, subsequent, immunohistochemistry, we noted that transplantable tumors growing in guinea pigs and rodents exhibit substantial deposits of fibrin in their stroma. Fibrin results from the clotting of fibrinogen, a 340kDa plasma protein which, under normal circumstances, is retained almost quantitatively within the blood vasculature. For fibrin to be deposited outside of blood vessels in tumor stroma, it was necessary that two requirements be met; namely, (1) that microvessels be abnormally hyperpermeable to permit the escape of fibrinogen and other plasma proteins necessary for blood clotting and (2) that there be a mechanism in place for activating the clotting system. In fact, both requirements were found to be met in tumors. The microvessels supplying tumors were hyperpermeable to fibrinogen and other plasma proteins, and both tumor cells and host stromal cells were capable of initiating extravascular coagulation via the tissue-factor pathway. Encouraged by these findings, we initiated a search for a tumor product that could account for tumor-vessels hyperpermeability. A potent vascular permeabilizing protein was soon found in serum-free tumor culture supernatants (Dvorak et al. 1979a,b) and was subsequently purified to homogeneity and given the name vascular permeability factor (VPF) (Senger et al. 1983, 1986, 1987, 1990).

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References

  • Abu-Jawdeh GM, Faix JD, Niloff J, Tognazzi K, Manseau E, Dvorak HF, Brown LF (1996) Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest 74:1105–1115.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT (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 LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen MS, Aiello LM, Ferrara N, King GL (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487.

    Article  PubMed  CAS  Google Scholar 

  • Alksne J (1959) The passage of colloidal particles across the dermal capillary wall under the influence of histamine. Q J Exp Physiol 44:51–66.

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Baluk P, Hirata A, Thurston G, Fujiwara T, Neal CR, Michel CC, McDonald DM (1997) Endothelial gaps:time course of formation and closure in inflamed venules of rats. Am J Physiol 272:L155–L170.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Bates DO, Curry FE (1996) Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol 271:H2520–H2528.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Boughton-Smith NK, Evans SM, Laszlo F, Whittle BJ, Moncada S (1993) The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat. Br J Pharmacol 110:1189–1195.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Breuing K, Eriksson E, Liu P, Miller DR (1992) Healing of partial thickness porcine skin wounds in a liquid environment. J Surg Res 52:50–58.

    Article  PubMed  CAS  Google Scholar 

  • Brock TA, Dvorak HF, Senger DR (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 

  • Brown LF, Chester JF, Malt RA, Dvorak HF (1987) Fibrin deposition in autochthonous Syrian hamster pancreatic adenocarcinomas induced by the chemical carcinogen N-nitroso-bis(2-oxopropyl)amine. J Natl Cancer Inst 78:979–986.

    PubMed  CAS  Google Scholar 

  • Brown LF, Asch B, Harvey VS, Buchinski B, Dvorak HF (1988a) Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas. Cancer Res 48:1920–1925.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Brown LF, Yeo K-T, Berse B, Yeo T-K, Senger DR, Dvorak HF, 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.

    Article  Google Scholar 

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR (1993a) 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 LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF (1993b) 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 LF, Yeo K-T, Berse B, Morgentaler A, Dvorak H, Rosen S (1995a) 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 Urol 154:576–579.

    Article  PubMed  CAS  Google Scholar 

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ (1995b) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26:86–91.

    Article  PubMed  CAS  Google Scholar 

  • Brown LF, Harrist TJ, Yeo KT, Stahle BM, Jackman RW, Berse B, Tognazzi K, Dvorak HF, Detmar M (1995c) Increased expression of vascular permeability factor (vascular endothelial growth factor) in bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme. J Invest Dermatol 104:744–749.

    Article  PubMed  CAS  Google Scholar 

  • Brown LF, Olbricht SM, Berse B, Jackman RW, Matsueda G, Tognazzi KA, Manseau EJ, Dvorak HF, Van De Water L (1995d) Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions. J Immunol 154:2801–2807.

    Google Scholar 

  • Brown LF, Tognazzi K, Dvorak H, 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 LF, Detmar M, Claffey K, Nagy J, Feng D, Dvorak A, Dvorak H (1997a) Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. In: Goldberg I, Rosen E (eds) Regulation of angioigenesis. Birkhauser, Basel.

    Google Scholar 

  • Brown LF, Detmar M, Tognazzi K, Abu-Jawdeh G, Iruela-Arispe ML (1997b) Uterine smooth muscle cells express functional receptors (flt-1 and KDR) for vascular permeability factor/vascular endothelial growth factor. Lab Invest 76:245–255.

    PubMed  CAS  Google Scholar 

  • Bundgaard M (1980) Transport pathways in capillaries - in search of pores. Annu Rev Physiol 42:325–336.

    Article  PubMed  CAS  Google Scholar 

  • Chow NH, Hsu PI, Lin XZ, Yang HB, Chan SH, Cheng KS, Huang SM, Su IJ (1997) Expression of vascular endothelial growth factor in normal liver and hepatocellular carcinoma:An immunohistochemical study. Hum Pathol 28:698–703.

    Article  PubMed  CAS  Google Scholar 

  • Claffey KP, Brown LF, del Aguila LF, Tognazzi K, Yeo KT, Manseau EJ, Dvorak HF (1996) Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res 56:172–181.

    PubMed  CAS  Google Scholar 

  • Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan Y-CE, Olander JV, Connolly DT, 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.

    Article  PubMed  CAS  Google Scholar 

  • Clementi F, Palade GE (1969) Intestinal capillaries. I. Permeability to peroxidase and ferritin. J Cell Biol 41:33–58.

    CAS  Google Scholar 

  • Colvin R, Dvorak H (1975) Role of the clotting system in cell-mediated hypersensitivity. II. Kinetics of fibrinogen/fibrin accumulation and vascular permeability changes in tuberculin and cutaneous basophil hypersensitivity reactions. J Immunol 114:377–387.

    CAS  Google Scholar 

  • Conn G, Bayne ML, Soderman DD, Kwok PW, Sullivan KA, Palisi TM, Hope DA, Thomas KA (1990a) 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478.

    Article  PubMed  CAS  Google Scholar 

  • Cullinan-Bove K, Koos RD (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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, Berse B, Dvorak HF (1994) Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180:1141–1146.

    Article  PubMed  CAS  Google Scholar 

  • Detmar M, Brown LF, Berse B, Jackman RW, Elicker BM, Dvorak HF, Claffey KP (1997) Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/ VEGF) and its receptors in human skin. J Invest Dermatol 108:263–268.

    Article  PubMed  CAS  Google Scholar 

  • Dewey WC (1959) Vascular-extravascular exchange of 131I plasma proteins in the rat. Am J Physiol 197:423–431.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Dvorak AM, Kohn S, Morgan ES, Fox P, Nagy JA, Dvorak HF (1996) The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J Leukoc Biol 59:100–115.

    PubMed  CAS  Google Scholar 

  • Dvorak HF (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 HF (1990) Leaky tumor vessels:consequences for tumor stroma generation and for solid tumor therapy. Prog Clin Biol Res 317–330

    Google Scholar 

  • Dvorak HF, Dvorak AM, Manseau EJ, Wiberg L, Churchill WH (1979a) 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.

    PubMed  CAS  Google Scholar 

  • Dvorak HF, Orenstein NS, Carvalho AC, Churchill WH, Dvorak AM, Galli SJ, Feder J, Bitzer AM, Rypysc J, Giovinco P (1979b) 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 HF, Senger DR, Dvorak AM (1983) Fibrin as a component of the tumor stroma:Origins and biological significance. Cancer Metastasis Rev 2:41–73.

    Article  PubMed  CAS  Google Scholar 

  • Dvorak HF, Harvey VS, McDonagh J (1984) 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 HF, Senger DS, Dvorak AM, Harvey VS, McDonagh J (1985) Regulation of extravascular coagulation by microvascular permeability. Science 227:1059–1061.

    Article  PubMed  CAS  Google Scholar 

  • Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM (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 HF, Sioussat TM, Brown LF, Nagy JA, Sotrel A, Manseau E, Van De Water L, Senger DR (1991a) Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors:concentration in tumor blood vessels. J Exp Med 174:1275–1278.

    Article  Google Scholar 

  • Dvorak HF, Nagy JA, Dvorak AM (1991b) Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3:77–85.

    PubMed  CAS  Google Scholar 

  • Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo KT, Yeo TK, Dvorak AM, van de Water L, Sioussat TM, Senger DR (1992) Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann N Y Acad Sci 667:101–111.

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Fava RA, Olsen NJ, Spencer GG, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF (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.

    Article  PubMed  CAS  Google Scholar 

  • Feng D, Nagy J, Hipp J, Dvorak H, Dvorak A (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.

    Article  PubMed  CAS  Google Scholar 

  • Feng D, Nagy J, Hipp J, Pyne K, Dvorak H, Dvorak A (1997) Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guinea-pig, mouse and rat: many are transcellular pores. J Physiol (Lond) 504:747–761.

    Article  CAS  Google Scholar 

  • Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. BBRC 161:851–858.

    PubMed  CAS  Google Scholar 

  • Ferrara N, Houck K, Jakeman L, Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13:18–32.

    PubMed  CAS  Google Scholar 

  • Filep JG, Foldes-Filep E (1993) Modulation by nitric oxide of platelet-activating factor-induced albumin extravasation in the conscious rat. Br J Pharmacol 110:1347–1352.

    PubMed  CAS  Google Scholar 

  • Frokjaer-Jensen J (1991) The endothelial vesicle system in cryofixed frog mesenteric capillaries analysed by ultrathin serial sectioning. J Electron Microsc Tech 19:291–304.

    Article  PubMed  CAS  Google Scholar 

  • Fujii E, Irie K, Uchida Y, Tsukahara F, Muraki T (1994) Possible role of nitric oxide in 5-hydroxytryptamine-induced increase in vascular permeability in mouse skin. Naunyn Schmiedebergs Arch Pharmacol 350:361–364.

    Article  PubMed  CAS  Google Scholar 

  • Fukumura D, Yuan F, Endo M, Jain RK (1997) Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions. Am J Pathol 150:713–725.

    PubMed  CAS  Google Scholar 

  • Gerlowski LE, Jain RK (1986) Microvascular permeability of normal and neoplastic tissues. Microvase Res 31:288–305.

    Article  CAS  Google Scholar 

  • Goldberg M, 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 JA, 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.

    Article  PubMed  CAS  Google Scholar 

  • Greenbaum LM, Semente G, Prakash A, Roffman S (1978) Leukokinins; their pharmacological properties and role in the pathology of fluid (ascites) accumulation. Agents Actions 8:80–84.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Guo D, Jia Q, Song HY, Warren RS, Donner DB (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 

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

    Google Scholar 

  • Hashimoto PH, Takaesu S, Chazono M, Amano T (1974) Vascular leakage through intraendothelial channels induced by cholera toxin in the skin of guinea pigs. Am J Pathol 75:171–180.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hatva E, Kaipainen A, Mentula P, Jaaskelainen J, Paetau A, Haltia M, 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 

  • Hirata A, Baluk P, Fujiwara T, McDonald DM (1995) Location of focal silver staining at endothelial gaps in inflamed venules examined by scanning electron microscopy. Am J Physiol 269.L403–418.

    Google Scholar 

  • Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (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.

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (1990) Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev 9:253–266.

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (1996) 1995 Whitaker Lecture: delivery of molecules, particles, and cells to solid tumors. Ann Biomed Eng 24:457–473.

    Article  PubMed  CAS  Google Scholar 

  • Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425.

    Article  PubMed  CAS  Google Scholar 

  • Joris I, Majno G, Lorey EJ, Lewis RA (1987) The mechanism of vascular leakage induced by leukotriene E4 endothelial contraction. Am J Pathol 126:19–24.

    PubMed  CAS  Google Scholar 

  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:290–298.

    PubMed  CAS  Google Scholar 

  • Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF (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.

    CAS  Google Scholar 

  • Karnovsky MJ (1967) The ultrastructural basis of capillary permeability studied with peroxidase as a tracer. J Cell Biol 35:213–236.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Li B, Weiner J, Houck K, 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 

  • Knighton DR, Hunt TK, Scheuenstuhl H, Halliday BJ, Werb Z, Banda MJ (1983) Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 221:1283–1285.

    Article  PubMed  CAS  Google Scholar 

  • Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, 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 JA, Dvorak HF, Dvorak AM (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 

  • Koos RD, 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 (abstract). J Cell Biol 115:421a.

    Google Scholar 

  • Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265:H586–592.

    Google Scholar 

  • Kubes P (1995) Nitric oxide affects microvascular permeability in the intact and inflamed vasculature. Microcirculation 2:235–244.

    Article  PubMed  CAS  Google Scholar 

  • Kubes P, Granger DN (1992) Nitric oxide modulates microvascular permeability. Am J Physiol 262:H611–615.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endege WO, Zhou F, Lee ME (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.

    Article  PubMed  CAS  Google Scholar 

  • Li J, Brown L, Hibbeerd M, Grossman J, Morgan J, Simons M (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270:H1803–1811.

    Google Scholar 

  • Lin K, Nagy JA, Xu H, Shockley TR, Yarmush ML, Dvorak HF (1994) Compartmental distribution of tumor-specific monoclonal antibodies in human melanoma xenografts. Cancer Res 54:2269–2277.

    PubMed  CAS  Google Scholar 

  • Maeda H, Noguchi Y, Sato K, Akaike T (1994) Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both new nitric oxide scavenger and nitric oxide synthase inhibitor. Jpn J Cancer Res 85:331–334.

    PubMed  CAS  Google Scholar 

  • Maillard JL, Pick E, Turk JL (1972) Interaction between ‘sensitized lymphocytes’ and antigen in vitro. V. Vascular permeability induced by skin-reactive factor. Int Arch Allergy 42:50–68.

    CAS  Google Scholar 

  • Majno G, Palade G, Schoefl G (1961) Studies on inflammation. II. The site of action of histamine and serotonin along the vascular tree: a topographic study. J Biophys Biochem Cytol 11:607–626.

    CAS  Google Scholar 

  • Majno G, Gilmore V, Leventhal M (1967) On the mechanism of vascular leakage caused by histamine type mediators. A microscopic study in vivo. Circ Res 21:833–847.

    CAS  Google Scholar 

  • Majno G, Shea SM, Leventhal M (1969) Endothelial contraction induced by histamine-type mediators: an electron microscopic study. J Cell Biol 42:647–672.

    Article  PubMed  CAS  Google Scholar 

  • Matsumura Y, Kimura M, Yamamoto T, Maeda H (1988) Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn J Cancer Res 79:1327–1334.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Michel CC (1988) Capillary permeability and how it may change. J Physiol (Lond) 404:1–29.

    CAS  Google Scholar 

  • Miles AA, Miles EM (1952) Vascular reaction to histamine, histamine-liberator, and leukotaxine in the skin of guinea pigs. J Physiol (Lond) 118:228–257.

    CAS  Google Scholar 

  • Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller N, Risau W, 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.

    Article  PubMed  CAS  Google Scholar 

  • Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS, Folkman J, Dvorak HF, Brown LF, Berse B, Yeo T-K, 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, Caro J (1994) Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 71:374–379.

    PubMed  CAS  Google Scholar 

  • Monacci WT, Merrill MJ, Oldfield EH (1993) Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264:C995–1002.

    Google Scholar 

  • Moor RM, Seamark RF (1986) Cell signaling, permeability, and microvasculatory changes during antral follicle development in mammals. J Dairy Sci 69:927–943.

    Article  PubMed  CAS  Google Scholar 

  • Morbidelli L, Chang CH, Douglas JG, Granger HJ, Ledda F, Ziche M (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 270:H411–415.

    Google Scholar 

  • Morris B, Sass M (1966) The formation of lymph in the ovary. Proc R Soc Lond Biol 164:577–591.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Murohara T, Horowitz JR, Silver M, Tsurumi Y, Chen D, Sullivan A, Isner JM Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 97:99–107.

    Google Scholar 

  • Nagy JA, Brown LF, Senger DR, Lanir N, Van De Water L, Dvorak AM, Dvorak HF (1988) Pathogenesis of tumor stroma generation:A critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta 948:305–326.

    Google Scholar 

  • Nagy JA, Herzberg KT, Dvorak JM, Dvorak HF (1993) Pathogenesis of malignant ascites formation: initiating events that lead to fluid accumulation. Cancer Res 53:2631–2643.

    PubMed  CAS  Google Scholar 

  • Nagy JA, Morgan E, Herzberg K, Manseau E, Dvorak A, Dvorak H (1995a) 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 JA, Masse EM, Herzberg KT, Meyers MS, Yeo K-T, Yeo T-K, Sioussat TM, Dvorak HF (1995b) Pathogenesis of ascites tumor growth. Vascular permeability factor, vascular hyperpermeability and ascites fluid accumulation. Cancer Res 55:360–368.

    PubMed  CAS  Google Scholar 

  • Nagy JA, Meyers MS, Masse EM, Herzberg KT, Dvorak HF (1995c) Pathogenesis of ascites tumor growth. Fibrinogen influx and fibrin accumulation in tissues lining the peritoneal cavity. Cancer Res 55:369–375.

    CAS  Google Scholar 

  • Nakano S, Matsukado K, Black KL (1996) Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide. Cancer Res 56:4027–4031.

    PubMed  CAS  Google Scholar 

  • Neal CR, Michel CC (1995) Transcellular gaps in microvascular walls of frog and rat when permeability is increased by perfusion with the ionophore A23187. J Physiol (Lond) 488:427–437.

    CAS  Google Scholar 

  • Neal C, Michel C (1996) Openings in frog microvascular endothelium induced by high intravascular pressure. J Physiol (Lond) 492:39–52.

    CAS  Google Scholar 

  • O’Connor SW, Bale WF (1984) Accessibility of circulating immunoglobulin G to the extravascular compartment of solid rat tumors. Cancer Res 44:3719–3723.

    PubMed  Google Scholar 

  • Okuda Y, Okamura H, Kanzaki H, Takenaka A, Morimoto K, Nishimura T (1980) An ultrastructural study of capillary permeability of rabbit ovarian follicles during ovulation using carbon tracer. Acta Obstet Gynecol Jpn 32:859–867.

    CAS  Google Scholar 

  • Olofsson B, Pajusola K, Kaipainen A, Voneuler G, Joukov V, Saksela O, Orpana A, Petersson RF, Alitalo K, Eriksson U (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581.

    Article  PubMed  CAS  Google Scholar 

  • Palade GE (1988) The microvascular endothelium revisited. In: Simionescu N, Simionescu M (eds) Endothelial cell biology in health and disease. Plenum, New York.

    Google Scholar 

  • Park J, Keller G-A, 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 

  • Payer A (1975) Permeability of ovarian follicles and capillaries in mice. Am J Anat 142:295–301.

    Article  PubMed  CAS  Google Scholar 

  • Pe’er J, Shweiki D, Itin A, Hemo I, Gnessin H, 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 

  • 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 USA 90:8915–8919.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Qu-Hong, Nagy JA, Senger DR, Dvorak HF, Dvorak AM (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.

    Article  PubMed  CAS  Google Scholar 

  • Quinn T, Peters K, DeVries C, Ferrara N, 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.

    Article  PubMed  CAS  Google Scholar 

  • Ramirez MM, Quardt SM, Kim D, Oshiro H, Minnicozzi M, Duran WN (1995) Platelet activating factor modulates microvascular permeability through nitric oxide synthesis. Microvasc Res 50:223–234.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Rippe B, Haraldsson B (1994) Transport of macromolecules across microvascular walls:the two-pore theory. Physiol Rev 74:163–219.

    Article  PubMed  CAS  Google Scholar 

  • Roberts WG, Hasan T (1993) Tumor-secreted vascular permeability factor/vascular endothelial growth factor influences photosensitizer uptake. Cancer Res 53:153–157.

    PubMed  CAS  Google Scholar 

  • Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108:2369–2379.

    PubMed  CAS  Google Scholar 

  • Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, 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 DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985.

    Article  PubMed  CAS  Google Scholar 

  • Senger DR, Perruzzi CA, Feder J, Dvorak HF (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 DR, Connolly D, Perruzzi CA, Alsup D, Nelson R, Leimgruber R, Feder J, Dvorak HF (1987) Purification of a vascular permeability factor (VPF) from tumor cell conditioned medium. Fed Proc 46:2102.

    Google Scholar 

  • Senger DR, Connolly DT, Van De Water L, Feder J, Dvorak HF (1990) Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50:1774–1778.

    Google Scholar 

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

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Shweiki D, Itin A, Neufeld G, Gitay GH, 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.

    Article  PubMed  CAS  Google Scholar 

  • Simionescu N (1983) Cellular aspects of transcapillary exchange. Physiol Rev 63:1536–1579.

    PubMed  CAS  Google Scholar 

  • Simon M, Grone HJ, Johren O, Kullmer J, Plate KH, Risau W, 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.

    Google Scholar 

  • Sioussat TM, Dvorak HF, Brock TA, Senger DR (1993) Inhibition of vascular permeability factor (vascular endothelial growth factor) with anti-peptide antibodies. Arch Biochem Biophys 301:15–20.

    Article  PubMed  CAS  Google Scholar 

  • Sobel A, LaGrue G (1980) Role of a vascular permeability-increasing factor released by lympyhocytes in renal pathology. Lymphokine Rep 1:211–230.

    CAS  Google Scholar 

  • Song CW, Levitt SH (1971) Quantitative study of vascularity in Walker carcinoma 256. Cancer Res 31:587–589.

    PubMed  CAS  Google Scholar 

  • Spar IL, Bale WF, Marrack D, Dewey WC, McCardle RJ, Harper PV (1967) 131I-labeled antibodies to human fibrinogen: diagnostic studies and therapeutic trials. Cancer 20:865–870.

    Article  PubMed  CAS  Google Scholar 

  • Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6:1677–1683.

    PubMed  CAS  Google Scholar 

  • Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. BBRC 187:1579–1586.

    PubMed  CAS  Google Scholar 

  • Tsurumi Y, Murohara T, Krasinski K, Chen D, Witzenbichler B, Kearney M, Couffinhal T, Isner JM (1997) Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med 3:879–886.

    Article  PubMed  CAS  Google Scholar 

  • van der Zee R, Murohara T, Luo Z, Zollmann F, Passeri J, Lekutat C, Isner JM (1997) Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium. Circulation 95:1030–1037.

    PubMed  Google Scholar 

  • Waltenberger J, Claesson WL, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Fltl, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995.

    PubMed  CAS  Google Scholar 

  • Warren BA (1979) The vascular morphology of tumors. In: Peterson H-I (ed) Tumor blood circulation:angiogenesis, vascular morphology and blood flow of experimental and human tumors. CRC Press, Boca Raton

    Google Scholar 

  • Watanabe Y, Dvorak HF (1997) Vascular permeability factor/vascular endothelial growth factor inhibits anchorage-disruption-induced apoptosis in microvessel endothelial cells by inducing scaffold formation. Exp Cell Res 233:340–349.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe Y, Lee SW, Detmar M, Ajioka I, Dvorak HF (1997) Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells. Oncogene 14:2025–2032.

    Article  PubMed  CAS  Google Scholar 

  • Weindel K, Moringlane JR, Marme D, Weich HA (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.

    Article  PubMed  CAS  Google Scholar 

  • Yeo T-K, Dvorak HF (1995) Tumor stroma. In: Colvin R, Bhan A, McCluskey R (eds) Diagnostic immunopathology. Raven, New York.

    Google Scholar 

  • Yeo K-T, Wang HH, Nagy JA, Sioussat TM, Ledbetter SR, Hoogewerf AJ, Zhou Y, Masse EM, Senger DR, Dvorak HF, 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 

  • Yoshiji H, Harris SR, Thorgeirsson UP (1997) Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res 57:3924–3928.

    PubMed  CAS  Google Scholar 

  • Yuan Y, Granger HJ, Zawieja DC, DeFily DV, Chilian WM (1993) Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. Am J Physiol 264:H1734–1739.

    Google Scholar 

  • Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, Jain RK (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756.

    PubMed  CAS  Google Scholar 

  • Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 93:14765–14770.

    Article  PubMed  CAS  Google Scholar 

  • Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, Bicknell R (1997) Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 99:2625–2634.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA

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

  2. Harvard Medical School, Boston, MA, 02215, USA

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

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  1. H. F. Dvorak
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  2. J. A. Nagy
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  3. D. Feng
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  5. A. M. Dvorak
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  1. Department of Medical Biochemistry and Microbiology Biomedical Center, University of Uppsala, Box 575, Uppsala, S-75123, Sweden

    Lena Claesson-Welsh

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Dvorak, H.F., Nagy, J.A., Feng, D., Brown, L.F., Dvorak, A.M. (1999). Vascular Permeability Factor/Vascular Endothelial Growth Factor and the Significance of Microvascular Hyperpermeability in Angiogenesis. In: Claesson-Welsh, L. (eds) Vascular Growth Factors and Angiogenesis. Current Topics in Microbiology and Immunology, vol 237. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59953-8_6

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