Objective:The purpose of this review is to propose a critical role for vascular endothelial growth factor (VEGF) in mediating the transfer of amniotic fluid from the amniotic compartment through the fetal membranes and fetal surface of the placenta into fetal blood.
Methods:Experimental findings in humans and animal models on the action of VEGF in mediating fluid transfer are reviewed and interpreted in order to postulate a proposed mechanism for VEGF regulation of amniotic fluid absorption through the fetal membranes and placenta.
Results:Recent scientific advances suggest that up-regulation of VEGF gene expression in the amnion and choiron is associated with increased transfer of amniotic fluid into fetal blood. The possible mechanisms of action for VEGF appear to involve regulation of intramembranous blood vessel proliferation and membrane transport via passive permeation as well as nonpassive transcytotic vesicular movement of fluid.
Conclusion:Currently evolving concepts suggest that amniotic fluid volume is regulated through modulation of the rate of intramembranous absorption of amniotic fluid by both passive and nonpassive mechanisms. The permediability factor VEGF appears to be a critical regulator of amniotic fluid trapsort in the fetal membranes.
1. Konduri GG, Fewell JE. Oligohydramnios. In: Brace RA, Ross MG, Robilliard JE, eds. Fetal and neonatal body fluids: The scientific basis for clinical practice. Perinatology Press, 1989;157-174.
2.
2. Healy DL. Polyhydramnios: An alternative hypothesis. In: Brace RA, Ross MG, Robilliard JE, eds. Fetal and neonatal body fluids: The scientific basis for clinical practice. Perinatology Press, 1989:175-185.
3.
3. Brace RA. Progress toward understanding the regulation of amniotic fluid volume: Water and solute fluxes in and through the fetal extraplacental membranes. Placenta1995;16:1-18.
4.
4. Gilbert WM, Brace RA. The missing link in amniotic fluid volume regulation: Intramembranous absorption. Obstet Gynecol1989;74:748-754.
5.
5. Ross MG, Brace RA. Amniotic fluid biology—basic and clinical aspects. J Matern Fetal Med2001;10:2-109.
6.
6. Gilbert WM, Brace RA. Novel determination of filtration coefficient of ovine placenta and intramembranous pathway. Am J Physiol1990;259:R1281-R1288.
7.
7. Jang PR, Brace RA. Amniotic fluid composition changes during urine drainage and tracheoesophagel occlusion in fetal sheep. Am J Obstet Gynecol1992;167:1732-1741.
8.
8. Matsumoto LC, Cheung CY, Brace RA. Effect of esophageal ligationon amniotic fluid volume and urinary flow rate in fetal sheep. Am J Obstet Gynecol2000;182:699-705.
9.
9. Faber JJ, Anderson DF. Regulatory response of intramembranous absorption of amniotic fluid to infusion of exogenous fluid in sheep. Am J Physiol1999;277:R236-R242.
10.
10. Matsumoto LC, Cheung CY, Brace RA. Prolonged hypoxia increases urinary flow without the development of polyhydramnios in the ovine fetus. Am J Obstet Gynecol2001;184:1008-1014.
11.
11. Daneshmand SS, Cheung CY, Brace RA, Regulation of amniotic fluid volume by intramembranous absorption in sheep: Role of passive permeability and vascular endothelial growth factor. Am J Obstet Gynecol2003;188:786-793.
12.
12. Ambramovich DR, Page KR. Pathways of water exchange in the fetoplacental unit at mid-pregnancy. J Obstet Gynecol Br Comonw1972;79:1099-1102.
13.
13. Gitlin D, Kumate J, Morales C, Noriega L, Arevalo N. The Turnover of amniotic fluid protein in the human conceptus. Am J Obset Gynecol1972;113:632-645.
14.
14. Heller L. Intrauterine amino acid feeding of the fetus. In: Bode H, Warshaw J, eds. Parenternal nutrition in infancy and childhood. Plenum Press, 1974:206-213.
15.
15. Schrder HJ, Dehne K, Andreas TH, Rago S, Rybakowshki CH. Diffusive transfer of water and glucose across the chorionic plate of the isolated human term placenta. Placenta1999;20:59-63.
16.
16. Reynolds WA, Pitkin RM, Hodaria AA. Transfer of iodide into amniotic fluid by the normal and the nephrectomized subhuman primate fetus. Am J Obstet Gynecol1969;104:633-641.
17.
17. Gilbert WM, EBy-Wilkens E, TAranal AF. The missing link in rhesus monkey amniotic fluid volume regulation: Intramembranous absorption. Obstet Gynecol1997;89:462-465.
18.
18. Brace RA, Gilbert WM, Thornburg KL. VAscularization of the ovine amnion and chorion: A morphometric characterization of the surface area of the intramembranous pathway. Am J Obstet Gynecol1992;161:1747-1755.
19.
19. Gilbert WM, Cheung CY, Brace RA. Rapid intramembranous absorption into the fetal circulation of arginine vasopressin injected intraamniotically. Am J Obstet Gynecol1991;164:1013-1020.
20.
20. Kullama LK, Agnew CL, Day L, Ervin MT, Ross MG. Ovine fetal swallowing and renal responses to oligohydramnios. Am J Physiol1994;266:R972-R978.
21.
21. Ross MG, Sherman Dj, Schreyer P, Ervin MG, Day L, Humme J. Fetal rehydration via intraamniotic fluid: Contribution of fetal swallowing. Pediatr Res1991;29:214-217.
22.
22. Leung DW, CAchianes G, Kuang WJ, Goeddle DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science1989;246:1306-1309.
23.
23. Conolly DT. VAscular permeability factor: A unique regulator of blood vessel function. J Cell Biochem1991;47:219-223.
24.
24. Senger DR, Perruzzi CA, Feder J, Dvorak HF. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. J Cancer Res1986;46:5629-5632.
25.
25. Terman BI, Dougher-Vermazne M, Carrion Me, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun1992;187:1579-1586.
26.
26. DeVries C, Escobedo JA, Ueno H, Houck K, Ferrera N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science1992;255:989-991.
27.
27. Ferrara N, Davis-Symth T. The biology of vascular endothelial growth factor. Endocr Rev1997;184:4-25.
28.
28. Sharkey AM, Charnock-Jones DS, Bocock CA, Brown KD, Smith Sk. Expressionof mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil1993;99:609-615.
29.
29. Jackson MR, Carney EW, Ley SJ, Ritchie JW. Localization of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta1994;15:341-353.
30.
30. Shiraishi S, Nakagawa K, Kinukawa N, Nakano H, Sueishi K. Immunochemical localization of vascular endothelial growth factor in the human placenta. Placenta1996;17:111-121.
31.
31. Ahmed A, Li XF, Dunk C, Whittle MJ, Rushton DI, Rollason T. Colocalisation of vascular endothelial growth factor and its Flt-1 receptor in human placenta. Growth Factors1995;12:235-243.
32.
32. Charnock-Jones DS, Sharkey AM, Boocock CA, Ahmed A, Pleven R, Ferrara N, Smith SK. VAscular endothelial growth factor receptor localization and activation in human trophoblast andchoriocarcinoma cells. Biol Reprod1994;51:524-530.
33.
33. Cooper JC, Sharkey AM, McLaren J, Charnock-Jones DS, Smith SK. Localization of vascular endothelial growth factor and its receptor, flt, in human placenta and decidua by immunohistochemistry. J Reprod Fertil1995;105:205-213.
34.
34. Clark DE, Smith SK, Sharley AM, Charnock-Jones DS. Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Hum Reprod1996;11:1090-1098.
35.
35. Vuckovic M, Ponting J, Terman BI, Niketic V, Seif MW, Kuman S. Expression of the vascular endothelial growth factor receptor KDR, in human placenta. J Anat1996;188:361-366.
36.
36. Bogic LV, Brace RA, Cheung CY. Cellular localization of vascular endothelial growth factor in ovince placenta and fetal membranes. Placenta2000;21:203-209.
37.
37. Barleon B, Hauser S, Schollman C, et al. Differential expression of the two VEGF receptors flt and KDR in placenta and vascular endothelial cells. J Cell Biochem1994;54:56-66.
38.
38. Winther H, Ahmed A, Dantzer V. Immunochemical localization of vascular endothelial growth factor (VEGF) and its two specific receptors, flt-1 and KDR, in the porcine placenta and non-pregnant uterus. Placenta1999;20:35-43.
39.
39. Cheung CY, Brace RA. Developmental expression of vascular endothelial growth factor and its receptors in ovine placenta and fetal membranes. J Soc Gynecol Investig1999;6:179-185.
40.
40. Bogic LV, Brace RA, Cheung CY. Developmental expression of vascular endothelial growth factor (VEGF) receptors and VEGF binding in ovine placenta and fetal membranes. Placenta2001;22:265-275.
41.
41. Cheung CY, Brace RA. Ovine vascular endothelial growth factor: Nucleotide sequence and expression in fetal tissues. Growth Factors1998;16:11-22.
42.
42. Hock KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vasacular endothelial growth factor family: Identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol1991;91:1806-1814.
43.
43. Charnock-Jones DS, Sharkey AM, Rajput-Williams J, et al. Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol Reprod1993;48:1120-1128.
44.
44. Anthony FW, Wheeler T, Elcock CL, Pickett M, Thomas EJ. Short report: Identification of a specific pattern of vascular endothelial growth factor mRNA expression in human placenta and cultured placental fibroblasts. Placenta1994;15:557-561.
45.
45. Cheung Cy, Singh M, Ebaugh MJ, Brace RA. Vascular endothelial growth factor gene expression in ovine placenta and fetal membranes. Am J Obstet Gynecol1995;173:753-759.
46.
46. Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev1992;13:18-32.
48. Vintzileos AM, Fleming AD, Scorza WE, et al. Relationship between fetal biophysical activities and umbilical cord blood gas values. Am J Obstet Gynecol1991;165:707-713.
49.
49. Cock ML, McCrabb Gj, Wlodek ME, Harding R. Effects of prolonged hypoxemia on fetal renal function and amniotic fluid volume in sheep. Am J Obstet Gynecol1997;176:320-326.
50.
50. Wlodek ME, Brace RA, Cock ML, Hooper SB, Harding R. Endocrine responses of fetal sheep to prolonged hypoxemia with and without acidemia: Relation to urine production. Am J Physiol1995;268:F868-F875.
51.
51. Brace RA, Wlodek ME, McCrabb GJ, Harding R. Swallowing and urine flow responses of the ovine fetus to 24 hours of hypoxia. Am J Physiol1994;266:R1345-R1352.
52.
52. Sherman DJ, Ross Mg, Day L, Humme J, Ervin MG. Fetal swallowing: Response to graded maternal hypoxemia. J Appl Physiol1991;71:1856-1861.
53.
53. Matsumoto LC, Bogic LV, Brace RA, Cheung CY. Prolonged hypoxia up-regulates vascular endothelial growth factor messenger RNA expression in ovine fetal membranes and placenta. Am J Obstet Gynecol2002;186:303-310.
54.
54. Brace RA. Fetal blood volume, urine flow, swallowing and amniotic fluid volume responses to long-term interavascular saline infusions. Am J Obstet Gynecol1989;161:1049-1054.
55.
55. Walker DW, Mitchell MD. Prostaglandins in urine of foetal lambs. Nature1978;271:161-162.
56.
56. Kelly EJ, Newell SJ, Brownlee KG, et al. Role of epidermal growth factor and transforming growth factor alpha in the developing stomach. Arch Dis Child Fetal Neonatal Ed1997;76:F158-F162.
57.
57. Varner MW, Dildy GA, Hunter C, Dudley Dj, Clark SL, Mitchell MD. Amniotic fluid epidermal growth factor levels in normal and abnormal pregnancies. J Soc Gynecol Investig1996;3:17-19.
58.
58. Koizumi N, Inatomi T, Sotozono C, Fullwood NJ, Quantock AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Current Eye Res2000;20:173-177.
59.
59. Kudolo GB, DeFronzo RA. Urinary platelet-activating factor excretion is elevated in non-insulin dependent diabetes mellitus. Prostaglandins Other Lipid Mediators1999;57:87-98.
60.
60. Fagerudd JA, Groop PH, Honkanen E, Teppo AM, Greonhagen-Riska C. Urinary excretion of TGF-beta 1, PDGF-BB and fibroectin in insulin-dependent diabetes mellitus patients. Kidney Int1997;63:S195-S197.
61.
61. Szabo A, Lutz J, Schleimer K, et al. Effect of angiotensin-converting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat. Kidney Int2000;57:982-991.
62.
62. Sawdy RJ, Slater DM, Dennes WJ, Sullivan MH, Bennett PR. The roles of the cyclooxygenases types one and two in prostaglandin synthesis in human fetal membranes at term. Placenta2000;21:54-57.
63.
63. Ben-Av P, Crofford LJ, Wilder RL, Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: A potential mechanism for infflammatory angiogenesis. FEBS Lett1995;372:83-87.
64.
64. Höper MM, Voelkel NF, Bates TO, et al. Prostaglandins induce vascular endothelial growth factor in a human monocytic cell line and rat lungs via cAMP. Am J Respir Cell Mol Biol1997;17:748-756.
65.
65. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: A model of glioblastoma multiforme pathophysiology. Mol Biol Cell1993;4:121-133.
66.
66. Gille J, Swerlick RA, Caughman SW. Transforming growth factor-α-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transpactivation. EMBO J1997;16:750-759.
67.
67. Petrovaara L, Kaipainen A, Mustonen T, et al. VAscular endothelial growth factor is induced in responses to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem1994;269:6271-6274.
68.
68. Ahmed A, Dearn S, Shams M, et al. Localization, quantification, and activation of platelet-activating factor receptor in human endometrium during the menstrual cycle: PAF stimulates NO, VEGF, and FAK. FASEB J1998;12:831-843.
69.
69. Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is down-regulated by corticosteroids. Am J Respir Cell Mol Biol1997;16:398-406.
70.
70. Drogi E, Wu T, Namiki A, Isner JM. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation1994;90:649-652.
71.
71. Williams B, Quinn-Baker A, Gallagher B. Serum and platelet-derived growth factor-induced expression of vascular permeability factor mRNA aby human vascular smooth muscle cells in vitro. Clin Sci1995;88:141-147.
72.
72. Perkins DJ, Kniss DA. Rapid and transient induction of cyclo-oxygenase 2 by epidermal growth factor in human amnion-derived WISH cells. Biochem J1997;321:677-681.
74. Smith SK, Kelly RW. Effect of platelet-activating factor on the release of PGF2α and PGE2 by separated cells of human endometrium. J Reprod Fertil1988;82:271-276.
75.
75. Alvi SA, Brown NL, Bennett PR, Elder MG, Sullivan MH. Corticotrophin-releasing hormone and platelet-activating factor induce transcription of the type-2 cyclo-oxygenase gene in human fetal membranes. Mol Hum Reprod1999;5:476-480.
76.
76. Ershov AV, Bazan NG. Induction of cyclooxygenase-2 gene expression in retinal pigment epithelium cells by photoreceptor rod outer segment phagocytosis and growth factors. J Neurosci Res1999;58:254-261.
77.
77. Ladoux A, Frelin C. Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun1993;195:1005-1010.
78.
78. Shweiki D, Itin A, Soffer D, Keshet E. VAscular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature1992;359:843-848.
79.
79. Minchenko A, Bauer T, Salceda A, Caro J. Hypoxic stimulation of vascular endothelial growth factor expression in viro and in vivo. Lab Invest1994;71:374-379.
80.
80. Liu Y, Cox SR, Morita T, Kourembnas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res1995;77:638-643.
81.
81. Ikeda E, Achen MG, Breier G, Risau W. Hyp0oxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C67 glioma cells. J Biol Chem1995;270:19761-19766.
82.
82. Shima DT, Deutsch U, D'Amore PA. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett1995;370:203-208.
83.
83. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem1996;271:2746-2753.
84.
84. Claffey KP, Shih SC, Mullen A, et al. Identification of human VPF/VEGF 3′ untranslated region mediating hypoxia-induced mRNA stability. Mol Biol Cell1998;9:469-481.
85.
85. Ji YS, Xu Q, Schmedtje JF Jr. Hypoxia induces high-mobility-group protein I (Y) and transcription of the cyclooxygenase-gene 2 in human vascular endothelium. Circ Res1998;83:295-304.
86.
86. Schmedtje JF Jr, YS Ji, Liu WL, Dubois RN, Runge MS. Hypoxia induces cyclooxygenase-2 via the NF-kappaB transcription factor in human vascular endothelial cells. J Biol Chem1997;272:601-608.
87.
87. Chida M, Voelkel NF. Effects of acute and chronic hypoxia on rat lung cyclooxygenase. Am J Physiol1996;270:L872-L878.
88.
88. Akiséu M, Keulteursay N, Coker I, Heuseyinov A. Plateletactivating factor is an important mediator in hypoxic ischemic brain injury in the newborn rat. Flunarizine and Ginkgo biloba extract reduce PAF concentration in the brain. Biol Neonate1998;74:439-444.
89.
89. Chen D, Chen W. Changes of distribution of platelet activating factor in the lung of rats with hypoxic pulmonary hypertension. Chin Med Sci J1996;109:776-779.
90.
90. Cai Y, Han M, Luo L, Song W, Zhou X. Increased expression of PDGF and c-myc genes in lungs and pulmonary arteris of pulmonary hypertensive rats induced by hypoxia. Chin Med Sci J1996;11:152-156.
91.
91. Berg JT, Breen EC, Fu Z, Mateu-Costello O, West JB. Alveolar hypoxia increases gene expression of extracellular matrix proteins and platelet-derived growth factor-36 in lung parenchyma. Am J Respir Crit Care Med1998;158:1920-1928.
92.
92. Starvi GT, Hong Y, Zachary IC, et al. Hypoxia and platelet-derived growth factor-36 synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth cells. FEBS Lett1995;358:311-315.
93.
93. Faber JJ, Anderson DF. Absorption of amniotic fluid by amniochorion in sheep. Am J Physiol2002;282:H850-H854.
94.
94. Parry-Jones E, Priya S. A study of the elasticity and tension of fetal membranes and of the relation of the area of the gestational sac to the area of the uterine cavity. Br J Obstet Gynaecol1976;83:205-212.
95.
95. Millar LK, Stollberg J, DeBuque L, Bryant-Greenwood G. Fetal membrane distention: Determination of the intrauterine surface area and distention of the fetal membranes preterm and at term. Am J Obstet Gynecol2000;182:128-134.
96.
96. Breier G. Angiogenesis in embryonic development—a review. Placenta2000;14:S11-S15.
97.
97. Ong S, Lash G, Baker PN. Angiogenesis and placental growth in normal and compromised pregnancies. Baillieres Clin Obstet Gynaecol2000;14:969-980.
99. Ku DD, Zaleski JK, Liu S, Brock TA. Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol1993;265:H586-H592.
100.
100. Yang HT, Yan Z, Abraham JA, Terjung RL. VEGF121- and 36 FGF-induced increase in collateral blood flow requires normal nitric oxide production. Am J Physiol2001;280:H1097-H1104.
101.
101. Banbury J, Siemionow M, Porvasnik S, Petras S, Browne E. Improved perfusion after subscrittical ischemia in muscle flaps treated with vascular endothelial growth factor. Plast Reconstr Surg2000;106:1541-1546.
102.
102. Cherng JM, Lin CM, Lin CL, et al. Effects of VEGF121 and/or VEGF165 gene transfection on collectral circulation development. J Forms Med Assoc2000;99:603-611.
103.
103. Hedriana HL, Brace RA, Gilbert WM. Changes in blood flow to the ovine chorion and amnion across gestation. J Soc Gynecol Investig1995;2:727-734.
104.
104. Lingwood BE, Wintour EM. Permeability of ovine amnion and amniochorion on urea and water. Obstet Gynecol1983;61:227-232.
105.
105. Wintour EM, Lingwood BE, Towstoless MK. Passive permeability of ovine amnion and allantois to chloride—gestational changes. Placenta1988;9:599-606.
106.
106. Michel CC. Capillaries, caveolae, calcium and cyclic nucleotides: A new look at microvascular permeability. J Mol Cell Cardiol1998;30:2541-2546.
108. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG. Caveolin, a protein component of caveolae membrane coats. Cell1992;68:673-682.
109.
109. Michel CC, Curry FE. Microvascular permeability. Physiol Rev1999;79:703-761.
110.
110. Bautzmann H, Schmidt W, Lemburg P. Experimental electron- and light-microscopical studies on the function of the amnion—apparatus of the check, the cat and man. Anat Anz1960;108:305-311.
111.
111. Armstrong WD, Wilt JC, Pritchard ET. VAculoation in the human amnion cell studied by time-lapse photography and electron microscopy. Am J Obstet Gynecol1968;102:932-948.
112.
112. King BF. Cell surface specializations and intercellular junctions in human amniotic epithelium: An electron microscopic and freeze-fracture study. Anat Rec1982;203:73-78.
113.
113. Shandley L, Alcorn D, Wintour EM. Ovine amniotic and allantoic epithelial across gestation. Anat Rec1997;248:542-553.
114.
114. Lyden TW, Anderson CL, Robinson JM. The endothelium but not the syncytiotrophoblast of human placenta expresses caveolae. Placenta2002;23:640-652.
115.
115. Houck KA, Leung DW, Rowland AM, Winter J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem1992;267:26031-26037.
116.
116. Bates DO, Curry FE. Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol1996;271:H2520-H2528.
117.
117. Fujii E, Irie K, Ohba KI, et al. Role of nitric oxide, prostaglandins and tyrosine kinase in vascular endothelial growth factorinduced increase in vascular permeability in mouse skin. Naunyn-Shmiedebergs Arch Pharmacol1997;365:475-480.
118.
118. Feng D, Nagy JA, Pyne K, Hammel I, Dvorak HF, Dvorak AM. Pathways of macromolecuular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation1999;6:23-44.
119.
119. Kohn S, Nagy J, Dvorak H, Dovrak A. Pathways of macromolecular trace transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab Invest1992;67:596-607.
120.
120. Vasile E, Hong Q, Dvorak HF, Dvorak AM. CAveolae and vesiculo/vacuolar organelles in bovine capillary endothelial cells cultured with VPF/VEGF on floating matrigel/collagen gels. J Histochem Cytochem1999;47:159-167.
121.
121. Chen J, Braet F, Brodsky S, et al. VEGF-induced mobilization of caveolae and increase in permeability of endothelial cells. Am J Physiol2002;282:C1053-C1063.
123. Feng Y, Venema VJ, Venema RC, Tsai N, Behzadian MA, Caldwell RB. VEGF-induced permeability increase is mediated by caveolae. Invest Ophthalmol Vis Sci1999;40:157-167.
124.
124. Liu J, Razani B, Tang S, Terman BI, Ware JA, Lisanti MP. Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells. J Biol Chem1999;274:15781-15785.
125.
125. Carmeliet P, Ferreira V, Briere G, et al. Abnormal blood vessel development and lethality in embryos loacking a single VEGF allele. Nature1996;380:435-439.
126.
126. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature1996;380:439-442.
127.
127. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood island formation and vasculogenesis in Flk-1 deficient mice. Nature1995;376:62-66.
128.
128. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature1995;376:66-70.
129.
129. Wang D, Donner DB, Warren RS. Homeostatic modulation of cell surface KDR and Flt1 expression an expression of the vascular endothelial cell growth factor (VEGF) receptor mRNAs by VEGF. J Biol Chem2000;275:15905-15911.
130.
130. Shen BQ, Lee DY, Gerber HP, Keyt BA, Ferrar N, Zioncheck TF. Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro. J Biol Chem1998;273:29979-29985.
