It has been proosed that endothelial cell activation is the primary event in the multisystem disorder of preeclampsia. Evidence for endothelial involvement in this condition abounds. The best-characterized morphologic abnonnality of this syndrome, glomerular endotheliosis, involves endothelial cells. Also associated with preeclampsia is a loss of endothelial cell integrity, with the consequent increase in vascular penneability, and an increase in the circulating levels of the endothelial cell markers, fibronection, von Willebrand factor, tissue plasminogen activator, and plasminogen activator inhibitor-1. It is now well documented that endothelial activation contributes to the coagulation abnormalities observed in this disease. There is much evidence that the endothelial alteractions in preeclampsia results from one or more circulating factors. The incubation of cultured endothelial cells with serum or plasma samples, taken from normal pregnant women and women with preeclampsia, results in marked alterations in cell behavior and metabolic processes. More recently, experiments employing myographic techniques have demonstrated convincingly the effects of a circulating factor(s) on the function of endothelial cells of resistance arteries. Vascular endothelial growth factor (VEGF) possesses many of the characteristics required of a candidate circulating factor. It contains a hydrophobic secretory signal sequence, exerts in vitro effects specific to vascular endothelial cell, and promotes endothelial expression of procoagulant activity. Circulating VEGF concentrations are elevated in women with preeclampsia, and VEGF increases microvascular endothelial cell prostacyclin production in a dose-dependent manner, analogous to the acute effects of plasma from patients with preeclampsia. Similarly, in myographic studies, when myometrial resistance arteries are incubated with VEGF, there are dose-dependent alterations in endothelium-dependent behavior, mirrorng those found after incubation with plasma from patients with preeclampsia.
1. Ferris TF. Pregnancy, preeclampsia, and the endothelial cell. N Engl J Med1991;325:1439-1442.
2.
2. Roberts JM. Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol1989;161:1200-1204.
3.
3. Spargo B, McCartney CP, Winemmiler R. Glomerular capillary endotheliosis in toxemia of pregnancy. Arch Pathol1959;68:593-599.
4.
4. Campbell DM, Campbell AJ. Evans blue disappearance rate in normal and preeclamptic pregnancy. Clin Exp Hypertens1983;2:163-169.
5.
5. Friedman SA, Taylor RN, Roberts JM. Pathophysiology of preeclampsia. Clin Perinatol1991;18:661-682.
6.
6. Taylor RN, Varma M, Teng NNH, Roberts JM. Women with preeclampsia have higher plasma endothelia levels than women with normal pregnancies. J Clin Endocrinol Metab1990;71:1675-1677.
7.
7. Mastrogiannis DS, O'Brien WF, Krammer J, Benoit R. Potential role of endothelins in normal and hypertensive pregnancies. Am J Obstet Gynecol1991;165:1711-1716.
8.
8. MacCumber MW, Ross CA, Glaser BM, Snyder SH. Endothelin: visualization of mRNAs by in situ hybridization provides evidence for local action. Proc Natl Acad SCi USA1989;86:7285-7289.
9.
9. Yoshimoto S, Ishizaki Y, Kurihara H, et al. Cerebral microvessel endothelium is producing endothelin. Brain Res1990;508:283-285.
10.
10. Roberts JM, Redman CWG. Preeclampsia: more than pregnancy induced hypertension. Lancet1993;341:1447-1451.
11.
11. Davies JA, Prentice CRM. Coagulation changes in pregnancy induced hypertension and growth retardation. In: Greer IA, Turpie AGG, Forbes CD, eds. Haemostasis and thrombosis in obstetrics and gynaecology. London: Chapman and Hall, 1992:143-162.
12.
12. Baker PN. The prediction of preeclampsia. Curr Obstet Gynaecol1993;3:69-74.
13.
13. Grant NF, Daley GL, Chand S, Whalley PJ, McDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest1973;52:2682-2689.
14.
14. McCarthy AL, Woolfson RG, Raju SK, Poston L. Abnormal endothelial cell function of resistance arteries in women with preeclampsia. Am J Obstet Gynecol1993;168:1323-1330.
15.
15. Knock GA, Poston L. Bradykinin-mediated relaxation of isolated maternal resistance arteries in normal and preeclampsia. Am J Obstet Gynecol1996;175:1668-1674.
16.
16. Ashworth JR, Warren AY, Baker PN, Johnson IR. Loss of endothelium-dependent relaxation in myometral resistance arteries in preeclampsia. Br J Obstet Gynaecol1997;104:1152-1158.
17.
17. Furchgott RF, Zawadski JV. The obligatory role of endothelial cells in the relaxation of smooth muscle by acetylcholine. Nature1980;288:373-376.
18.
18. Palmer RMJ, Ferrige AG, Maconda S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature1987;327:524-526.
19.
19. Ignarro LJ, Buga GM, Woodss KS. Byrns RE, Chaudhari G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA1998;94:9265-9269.
20.
20. Kuriyama H, Suzuki H. The effects of acetylcholine on the membrane and contractile properties of smooth muscle cells of the rabbit superior mesenteriic artery. Br J Pharmacol1978;64:493-501.
21.
21. Bolton TB, Lang RJ, Takewaki T. Mechanism of action of noradrenaliine and carbachol on smooth muscle guinea-pig anterior mesenteric artery. J Physiol1984;351:549-572.
22.
22. Nakashima M, Mombouli JV, Taylor A, Vanhoutte PM. Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries. J Clin Invest1993;23:747-756.
23.
23. Randall MD, Alexander SPH, Bennett TE, et al. An Endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Commun1996;229:114-120.
24.
24. Ashworth JR, Baker PN, Warren AY, Johnson IR. The mechanisms of endothelium-dependent relaxation in myometrial resistance vessels and their alterations in preeclampsia. Hypertens Pregnancy1998; in press.
25.
25. Page EW. The relation between hydatidiform moles, relative ischaemia of the gravid uterus, and placental origin of preeclampsia. Am J Obst Gynecol1939;37:291-293.
26.
26. Rodgers GM, Taylor RN, Roberts JM. Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells. Am J Obstet Gynecol1988;159:908-914.
27.
27. Tsukimori K, Maeda H, Shingu M, Koyanagi T, Nobunaga M, Nakano H. The possible role of endothelial cells in hypertensive disorders during pregnancy. Obstet Gynecol1992;80:229-233.
28.
28. Lorentzen B, Endersen T, Hovig E, et al. Sera from preeclamptic women increases the content of triglycerides and reduces the release of prostacyclin in cultured endothelial cells. Thromb Res1991;63:363-372.
29.
29. Baker PN, Davige ST, Roberts JM. Plasma from women with preeclampsia increases endothelial cell nitric oxide production. Hypertension1995;26:244-248.
30.
30. de Groot CJ, Davidge ST, Friedman SA, McLaughlin MK, Roberts JM. Taylor RN. Plasma from preeclamptic women increases human endothelial cell prostacyclin production without changes in cellular enzyme activity or mass. Am J Obstet Gynecol1995;172:976-985.
31.
31. Hayman R, Sattar N, Warren AY, Greer I, Johnson I, Baker PN. A relationship between myometrial resistance artery behavior and circulating lipid composition. Am J Obstet Gynecol1998; in press.
32.
32. Ashworth JR, Warren AY, Johnson IR, Baker PN. Plasma from preeclamptic women and functional change in myometrial resistance arteries. Br J Obstet Gynaecol1998;4:459-461.
33.
33. Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evidence of endothelial dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens1991;4:700-708.
34.
34. RRoberts JM, Edep ME, Goldfein A, Taylor RN. Sera from preeclamptic women specifically ativate human umbilical vein endothelial cells in vitro. Am J Reprod Immunol1992;27:101-108.
35.
35. Taylor RN, Musci TJ, Rodgers GM, Roberts JM. Preeclamptic sera stimulate increased platelet-derived growth factor mRNA and protein expression by cultured human endothelial cells. Am J Reprod Immunol1991;25:105-108.
36.
36. Haller H, HHempel A, Homuth V, et al. Endothelil-cell permeability and protein kinase C in preeclampsia. Lancet1998;351:945-949.
37.
37. Myatt L. Ecosanoids and blood pressure regulation. In: Sharp F, Symonds EM, eds. Hypertension in pregnancy: proceedings of the 16th Study Group of the RCOG. New York: Perinatology Press, 1987.
38.
38. Brown MA, Tibben E, Zammit VC, Cario GM, Carlton MA. Nitric oxide excretion in normal and hypertensive pregnancies. Hypertens Pregnancy1995;14:319-326.
39.
39. Wellings RP, Brockelsby JC, Baker PN. Activation of endothelial cells by plasma from women with preeclampsia: differential effects of four endothelial cell types. J Soc Gynecol Invest1998;5:31-37.
40.
40. Baker PN, Davidge ST, Barankiewizc J, Roberts JM. Plasma of preeclamptic women initially stimulates then inhibits endothelial prostacyclin production. Hypertension1996;27:56-61.
41.
41. Davidge ST, Baker PN, McLaughlin MM, Roberts JM. Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. Circ Res1995;77:274-283.
42.
42. Fox PL, DiCorleto PE. Regulation of production of a platelet derived growth factor-like protein by cultured bovine aortic endothelial cells. J Cell Physiol1984;121:298-308.
43.
43. Sattar N, Bendomir A, Berry C, Shepherd J, Greer IA, Packard CJ. Lipoprotein subfractions in preeclampsia: pathogenic parallels to atherosclerosis. Obstet Gynecol1997;89:403-408.
44.
44. Hayman R, Brockelsby J, Warren A, Ashworth J, Johnson I, Baker P. Evidence for a circulating factor in preeclampsia. A role for vascular endothelial growth factor?Br J Obstet Gynaecol1998;105:39-40.
45.
45. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak Hf. Tumor cells secret a vascular permeability factor that promotes accumulation of ascites fluid. Science1983;219:983-985.
46.
46. Miles AA, Miles EM. Vascular reactions to histamine, histamine liberator and leukotaxine in the skin of guinca-pigs. J Physiol1952;118:228-257.
47.
47. Connolly DT, Heuvelman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest1989;84:1470-1478.
48.
48. Ferrar 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.
49.
49. Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science1989;246:1309-1312.
50.
50. Terman BI, Dougher-Vermazen 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.
51.
51. Vaisman N, Gospodarowicz D, Neufeld G. Characterization of the receptors for vascular endothelial growth factor. J Biol Chem1990;19461-6-6.
52.
52. Murohara T, Horowitz JR, Silver M, et al. Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation1998;97:97-107.
53.
53. Baker PN, Krasnow J, Roberts JM, Yeo KT. Elevated serom levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol1995;86:815-821.
54.
54. Sharkey AM, Cooper JC, Balmforth JR, et al. Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by preeclampsia. Eur J Clin Invest1996;26:1182-1185.
55.
55. Brockelsby JC. Anthony F, Johnson IRJ, Wheeler T, Baker PN. Increased serum vascular endotelial growth factor concentrations in pre-eclampsia. Hypertens Pregnancy1998;17:283-290.
56.
56. Wheeler T, Brockelsby J, Wellings RP, Anthony F, Evans P, Baker PN. Serum levels of vascular endothelial growth factor are raised in preeclamptic versus normotensive pregnant women. J Soc Clin Invest1997;4:194A-194A.
57.
57. Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in preeclampsia. Br J Obstet Gynaecol1997;104:223-228.
58.
58. Anthony FW, Evans PW. Wheeler T, Wood PJ. Variation in detection of VEGF in maternal serum by immunoassay and the possible influence of binding proteins. Ann Clin Biocem1997;34:276-280.
59.
59. Banks RE, Forbes MA, Searles J, et al. Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1. Mol Hum Reprod1998;4:377-386.
60.
60. Jackson MR, Carney EW, Lye SJ, Knox Ritchie JW. Localisation of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta1994;15:341-353.
61.
61. Taylor CM, Stevens H, Anthony FW, Wheeler T. Influence of hypoxia on vascular endothelial growth factor and chorionic gonadotrophin production in the trophoblast-derived cell lines: JEG, JAr and BeWo. Placenta1997;18:451-458.
62.
62. Redman CWG, Beilin LJ, Bonnar J. Renal function in preeclampsia. J Clin Pathol1976;10:91-94.
63.
63. Tsurumi Y, Murohara T, Krainski K et al. Reciprocal relation between VEGF and NO in the regulation of endotehlial integrity. Nature Med1997;3:879-886.
64.
64. Wu HM, Huang Q, Yuan Y, Granger HJ. VEGF induces No-dependent hyperpermeability in coronary venules. Am J Physiol1996;271:h2735-h2739.
65.
65. Ni Y, May V, Braas K, Osol G. Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects. Am J Physiol1997;273:H938-H944.
66.
66. Ahmed A, Dunk C, Kniss D, Wilkes M. Role of VEGF receptor-1 (Flt-1) in mediating calcium-dependent nitric oxide release and limiting DNA synthesis in human trophoblast cells. Lab Invest1997;76:779-791.
68. Davidge ST, Signorella AP, Hubel CA, Lykins DL, Roberts JM. Distinct factors in plasma of preeclamptic women increase endothelial nitric oxide or prostacyclin. Hypertenson1996;28:758-764.
69.
69. Brockelsby J, Hayman R, Warren A, Jonson I, Baker P. Preeclampsia: a role for vascular endothelial growth factor. J Soc Gynecol Invest1998;5:67A-67A.
70.
70. Grant JM. Confusion with Doppler, certainty with salt, and more basic science needed in preeclampsia. Br J Obstet Gynaecol1998;105:v-v.
