New aspects in the pathophysiology of preeclampsia.

Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.

[1]  Lewis H Kuller,et al.  Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. , 2004, American journal of physiology. Heart and circulatory physiology.

[2]  J. Granger,et al.  L-Arginine Attenuates Hypertension in Pregnant Rats With Reduced Uterine Perfusion Pressure , 2004, Hypertension.

[3]  G. Remuzzi,et al.  l-Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species , 2004, Hypertension.

[4]  K. Lim,et al.  Circulating angiogenic factors and the risk of preeclampsia. , 2004, The New England journal of medicine.

[5]  Robert N. Taylor,et al.  First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. , 2004, The Journal of clinical endocrinology and metabolism.

[6]  A. Jeyabalan,et al.  Essential Role for Vascular Gelatinase Activity in Relaxin-Induced Renal Vasodilation, Hyperfiltration, and Reduced Myogenic Reactivity of Small Arteries , 2003, Circulation research.

[7]  J. Foidart,et al.  Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. , 2003, The Journal of clinical endocrinology and metabolism.

[8]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[9]  D. Saller,et al.  Second‐Trimester Maternal Serum Placental Growth Factor and Vascular Endothelial Growth Factor for Predicting Severe, Early‐Onset Preeclampsia , 2003, Obstetrics and gynecology.

[10]  A. Hingorani,et al.  Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia , 2003, The Lancet.

[11]  S. Fisher,et al.  The Human Placenta Remodels the Uterus by Using a Combination of Molecules That Govern Vasculogenesis or Leukocyte Extravasation , 2003, Annals of the New York Academy of Sciences.

[12]  Y. Taketani,et al.  Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. , 2003, The Journal of clinical endocrinology and metabolism.

[13]  G. Prescott,et al.  Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study , 2003, BMJ : British Medical Journal.

[14]  Y. Matsui,et al.  VEGF-mediated angiogenesis is impaired by angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts. , 2003, Cardiovascular research.

[15]  G. Wallukat,et al.  AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase , 2003, Circulation.

[16]  A. Luttun,et al.  Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? , 2003, The Journal of clinical investigation.

[17]  T. Libermann,et al.  Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia , 2003 .

[18]  J. Haigh,et al.  Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. , 2003, The Journal of clinical investigation.

[19]  K. Conrad,et al.  Impaired Oxygen-dependent Reduction of HIF-1α and -2α Proteins in Pre-eclamptic Placentae , 2003 .

[20]  Y. Pinto,et al.  Increased expression of cardiac angiotensin II type 1 (AT(1)) receptors decreases myocardial microvessel density after experimental myocardial infarction. , 2003, Cardiovascular research.

[21]  S. Bobst,et al.  Maternal Autoantibodies From Preeclamptic Patients Active Angiotensin Receptors on Human Trophoblast Cells , 2003, The Journal of the Society for Gynecologic Investigation: JSGI.

[22]  K. Conrad,et al.  Impaired oxygen-dependent reduction of HIF-1alpha and -2alpha proteins in pre-eclamptic placentae. , 2003, Placenta.

[23]  清水 紀宏 VEGF-mediated angiogenesis is impaired by angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts , 2003 .

[24]  Robert N. Taylor,et al.  Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. , 2003, American journal of obstetrics and gynecology.

[25]  F. Kabbinavar,et al.  Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  J. Pouysségur,et al.  Induction of Hypoxia-inducible Factor-1α by Transcriptional and Translational Mechanisms* , 2002, The Journal of Biological Chemistry.

[27]  G. Wallukat,et al.  Potential Role of Autoantibodies Belonging to the Immunoglobulin G-3 Subclass in Cardiac Dysfunction Among Patients With Dilated Cardiomyopathy , 2002, Circulation.

[28]  H. Dvorak Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  K. Conrad,et al.  Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  N. Sattar,et al.  Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? , 2002, BMJ : British Medical Journal.

[31]  R. Schmieder,et al.  Angiotensin Converting Enzyme Inhibition and Angiotensin II AT1-Receptor Blockade Reduce the Levels of Asymmetrical NG, NG-Dimethylarginine in Human Essential Hypertension* , 2002 .

[32]  K. Alitalo,et al.  Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. , 2002, The American journal of pathology.

[33]  A. Hsueh,et al.  Activation of Orphan Receptors by the Hormone Relaxin , 2002, Science.

[34]  R. T. Lie,et al.  Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. , 2001, BMJ : British Medical Journal.

[35]  H. Lother,et al.  Increased AT1 receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness , 2001, Nature Medicine.

[36]  D. Grobbee,et al.  Excessive Urinary Albumin Levels Are Associated With Future Cardiovascular Mortality in Postmenopausal Women , 2001, Circulation.

[37]  J. Pell,et al.  Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129 290 births , 2001, The Lancet.

[38]  K. Conrad,et al.  Relaxin is essential for renal vasodilation during pregnancy in conscious rats. , 2001, The Journal of clinical investigation.

[39]  C. Redman,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Expression of Inflammatory Cytokines in Placentas from Women with Preeclampsia* , 2022 .

[40]  K. Conrad,et al.  Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[41]  D. Ganten,et al.  Rats transgenic for human renin and human angiotensinogen as a model for gestational hypertension. , 2000, Journal of the American Society of Nephrology : JASN.

[42]  K. Conrad,et al.  Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[43]  G. Wallukat,et al.  Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension , 2000, Journal of hypertension.

[44]  S. Gardiner,et al.  Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia , 2000, Nature.

[45]  G. Wallukat,et al.  AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. , 2000, Circulation.

[46]  M. Radomski,et al.  Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries. , 2000, American journal of physiology. Heart and circulatory physiology.

[47]  K. Conrad,et al.  Expression of endothelial nitric oxide synthase by extravillous trophoblast cells in the human placenta. , 2000, Placenta.

[48]  M. Marrero,et al.  Vascular Endothelial Growth Factor Signals Endothelial Cell Production of Nitric Oxide and Prostacyclin through Flk-1/KDR Activation of c-Src* , 1999, The Journal of Biological Chemistry.

[49]  K. Conrad,et al.  Plasma and 24-h NO(x) and cGMP during normal pregnancy and preeclampsia in women on a reduced NO(x) diet. , 1999, The American journal of physiology.

[50]  K. Conrad,et al.  Plasma and 24-h NOx and cGMP during normal pregnancy and preeclampsia in women on a reduced NOx diet. , 1999, American journal of physiology. Renal physiology.

[51]  M. Post,et al.  Inhibition of TGF-beta 3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies. , 1999, The Journal of clinical investigation.

[52]  M. Hod,et al.  Microalbuminuria after pregnancy complicated by pre-eclampsia. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[53]  D. Charnock-Jones,et al.  Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity. , 1999, Molecular endocrinology.

[54]  G. Wallukat,et al.  Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. , 1999, The Journal of clinical investigation.

[55]  M. Goligorsky,et al.  CO‐OPERATION BETWEEN ENDOTHELIN AND NITRIC OXIDE IN PROMOTING ENDOTHELIAL CELL MIGRATION AND ANGIOGENESIS , 1999, Clinical and experimental pharmacology & physiology.

[56]  K. Conrad,et al.  Relaxin is a potent renal vasodilator in conscious rats. , 1999, The Journal of clinical investigation.

[57]  K. Conrad,et al.  Circulating Levels of Immunoreactive Cytokines in Women with Preeclampsia , 1998, American journal of reproductive immunology.

[58]  M. Drab,et al.  Endothelial-cell permeability and protein kinase C in pre-eclampsia , 1998, The Lancet.

[59]  M. Lindheimer,et al.  Preeclampsia selectively impairs endothelium-dependent relaxation and leads to oscillatory activity in small omental arteries. , 1998, The Journal of clinical investigation.

[60]  F. Gejyo,et al.  Postpartum renal lesions in women with pre-eclampsia. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[61]  K. Lim,et al.  Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. , 1997, The American journal of pathology.

[62]  C. Damsky,et al.  Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? , 1997, The Journal of clinical investigation.

[63]  E. Dejana,et al.  Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? , 1997, The Journal of clinical investigation.

[64]  A. Busjahn,et al.  Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients. , 1997, Hypertension.

[65]  E. Amento,et al.  Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. , 1996, The Journal of clinical investigation.

[66]  K. Conrad,et al.  Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. , 1995, The Journal of clinical investigation.

[67]  A. Zanchetti,et al.  Atrial natriuretic peptide and hemodynamic changes during normal human pregnancy. , 1995, Hypertension.

[68]  R. Kendall,et al.  Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[69]  L. Rochelle,et al.  Identification of increased nitric oxide biosynthesis during pregnancy in rats , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[70]  C. Damsky,et al.  Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. , 1993, The Journal of clinical investigation.

[71]  T. Benedetti,et al.  The Maternal Hemodynamic Effect of Indomethacin in Normal Pregnancy , 1992, Obstetrics and gynecology.

[72]  K. Conrad,et al.  Plasma level, urinary excretion, and metabolic production of cGMP during gestation in rats. , 1989, The American journal of physiology.

[73]  L. Moore,et al.  Blunted vasoreactivity in pregnant guinea pigs is not restored by meclofenamate. , 1989, American journal of obstetrics and gynecology.

[74]  C. Baylis Renal effects of cyclooxygenase inhibition in the pregnant rat. , 1987, The American journal of physiology.

[75]  K. Conrad,et al.  Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats. , 1986, The Journal of clinical investigation.

[76]  E. Gallery,et al.  Are the renal functional changes of human pregnancy caused by prostacyclin? , 1985, Prostaglandins.

[77]  K. Conrad,et al.  Renal hemodynamics during pregnancy in chronically catheterized, conscious rats. , 1984, Kidney international.

[78]  R. Osathanondh,et al.  Relaxin in Normal and Pathogenic Pregnancies , 1982, Obstetrics and gynecology.

[79]  A. Donker,et al.  Prostaglandin E2, plasma renin activity, and renal function throughout rabbit pregnancy. , 1982, The Journal of laboratory and clinical medicine.

[80]  J. Elema,et al.  MORPHOLOGICAL CHANGES OF THE SPIRAL ARTERIES IN THE PLACENTAE BED IN RELATION TO PRE‐ECLAMPSIA AND FETAL GROWTH RETARDATION , 1981, British journal of obstetrics and gynaecology.

[81]  J. Tucci,et al.  Urinary excretion of cyclic 3',5'-adenosine monophosphate and cyclic 3',5'-guanosine monophosphate during and after pregnancy. , 1977, The Journal of clinical endocrinology and metabolism.

[82]  L. Chesley,et al.  The remote prognosis of eclamptic women. , 1976, American heart journal.

[83]  L. Chesley,et al.  The remote prognosis of eclamptic women. Sixth periodic report. , 1976, American journal of obstetrics and gynecology.