FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2051203706> ?p ?o ?g. }

• W2051203706 endingPage "837" @default.
• W2051203706 startingPage "831" @default.
• W2051203706 abstract "Preeclampsia is a systemic disease that results from placental defects and occurs in about 5–8% of pregnancies worldwide. Preeclampsia is a disease of many theories, wherein investigators put forward their favorite mechanistic ideas, each with a causal appeal for the pathogenesis of preeclampsia. In reality, the patho-mechanism of preeclampsia remains largely unknown. Preeclampsia, as diagnosed in patients today, is likely a heterogeneous collection of disease entities that share some common features but also show important differences. Therefore, one single mechanism may never be found to explain all the variants of preeclampsia. Current research must focus on evaluating such diverse mechanisms, as well as the possible common effector pathways. Here, we provide a discussion of several possible mechanisms and putative theories proposed for preeclampsia, with particular emphasis on the recent discovery of a new genetic mouse model offering new opportunities to explore experimental therapies. Preeclampsia is a systemic disease that results from placental defects and occurs in about 5–8% of pregnancies worldwide. Preeclampsia is a disease of many theories, wherein investigators put forward their favorite mechanistic ideas, each with a causal appeal for the pathogenesis of preeclampsia. In reality, the patho-mechanism of preeclampsia remains largely unknown. Preeclampsia, as diagnosed in patients today, is likely a heterogeneous collection of disease entities that share some common features but also show important differences. Therefore, one single mechanism may never be found to explain all the variants of preeclampsia. Current research must focus on evaluating such diverse mechanisms, as well as the possible common effector pathways. Here, we provide a discussion of several possible mechanisms and putative theories proposed for preeclampsia, with particular emphasis on the recent discovery of a new genetic mouse model offering new opportunities to explore experimental therapies. Preeclampsia is a devastating pregnancy-associated disorder characterized by the onset of hypertension, proteinuria, and edema. Despite intensive investigation, our current understanding of the pathophysiology is limited. Emergent delivery of the baby alleviates the maternal symptoms of preeclampsia, but may lead to increased morbidity for the baby secondary to iatrogenic prematurity. It is estimated that about 15% of preterm births are because of preeclampsia. In screening for this disease, hypertension associated with pregnancy is a useful clinical feature; however, it is not a specific finding and is often confused with gestational hypertension. Preeclampsia affects about 5–8% of all pregnant women. Surprisingly, the incidence of preeclampsia has increased in recent years1.Martin J. Hamilton B. Sutton P. et al.Births: final data for 2006.Natl Vital Stat Rep. 2009Google Scholar and may be much higher in developing countries. Recent speculations on the pathogenesis of preeclampsia are mainly focused on the maternal symptoms of preeclampsia. However, such attempts have failed to consider an important feature of this disease: except in special cases (such as postpartum preeclampsia), preeclampsia is a pregnancy-induced disease that originates in the ‘hypoxic placenta’. Eclampsia has been recognized clinically since the time of Hippocrates. Two thousand years ago, Celsus described pregnancy-associated seizures that disappeared after delivery of the baby. Because these symptoms emerged without any warning signs, the condition was named ‘eclampsia’, the Greek word for ‘lightning’. In the mid-nineteenth century, Rayer and Lever2.Lever J.C.W. Cases of puerperal convulsions, with remarks.Guy's Hosp Rep. 1843; 1: 495-517Google Scholar,3P. Rayer Traité des Maladies des Reins et des Altérations Sécrétion Urinaire (3 vols.). JB Bailliére: Paris 1839–1841Google Scholar described the association of proteinuria with eclampsia. In 1884, Schedoff and Porockjakoff first observed the link between hypertension and eclampsia. Based on these early observations, physicians and scientists in the twentieth century began to realize that proteinuria and hypertension were strong predictive indicators for the onset of eclampsia. This prequel of eclampsia was termed preeclampsia.4.Cook H. Briggs J. Clinical observations on blood pressure.Johns Hopkins Hosp Rep. 1903; 11: 451-455Google Scholar Hypertension in preeclampsia can lead to serious complications in both maternal and neonatal health. However, the etiology of hypertension in preeclampsia remains unclear. In normal human pregnancy, there is increased cardiac output with expanded circulatory volume and a decrease in peripheral vascular resistance (Figure 1).5.Cope I. Plasma and blood volume changes in pregnancies complicated by pre-eclampsia.J Obstet Gynaecol Br Commonw. 1961; 68: 413-416Crossref PubMed Scopus (10) Google Scholar,6.MacGillivray I. Rose G.A. Rowe B. Blood pressure survey in pregnancy.Clin Sci. 1969; 37: 395-407PubMed Google Scholar During normal human gestation, blood pressure is slightly decreased (with minimal changes in systolic pressure but with evident decrease in diastolic blood pressure) because of the dilation of maternal vessels (Figure 1).6.MacGillivray I. Rose G.A. Rowe B. Blood pressure survey in pregnancy.Clin Sci. 1969; 37: 395-407PubMed Google Scholar Such vessel dilation allows for fluid expansion in the mother and helps protect against placental hypoperfusion (Figure 1).7.Visser W. Wallenburg H.C. Maternal and perinatal outcome of temporizing management in 254 consecutive patients with severe pre-eclampsia remote from term.Eur J Obstet Gynecol Reprod Biol. 1995; 63: 147-154Abstract Full Text PDF PubMed Scopus (86) Google Scholar However, in preeclamptic pregnancy, plasma volume is significantly decreased despite the presence of massive edema.5.Cope I. Plasma and blood volume changes in pregnancies complicated by pre-eclampsia.J Obstet Gynaecol Br Commonw. 1961; 68: 413-416Crossref PubMed Scopus (10) Google Scholar As a result, there is reduced systemic perfusion, which can potentially lead to damage of both the maternal organs and those of the baby8.Redman C.W. Maternal plasma volume and disorders of pregnancy.Br Med J (Clin Res Ed). 1984; 288: 955-956Crossref PubMed Scopus (27) Google Scholar (Figure 1). In preeclamptic women, plasma renin activity (PRA) is lower when compared with that of normal pregnant women9.Brown M.A. Zammit V.C. Mitar D.A. et al.Renin-aldosterone relationships in pregnancy-induced hypertension.Am J Hypertens. 1992; 5: 366-371Crossref PubMed Scopus (61) Google Scholar (Figure 1). Renin, a key enzyme in the renin–angiotensin system, acts as a volume sensor, and lower PRA has been associated with expansion of circulatory volume.10.Blumenfeld J.D. Laragh J.H. Management of hypertensive crises: the scientific basis for treatment decisions.Am J Hypertens. 2001; 14: 1154-1167Crossref PubMed Scopus (86) Google Scholar Does PRA suppression in preeclampsia simply suggest that preeclampsia is associated with volume-dependent hypertension? The answer is not clear at this point and more studies are required. In preeclampsia, increased vascular sensitivity for vasoactive substances, such as angiotensin II, is reported11.Gant N.F. Daley G.L. Chand S. et al.A study of angiotensin II pressor response throughout primigravid pregnancy.J Clin Invest. 1973; 52: 2682-2689Crossref PubMed Scopus (1012) Google Scholar (Figure 1). In addition, an increasing number of studies suggest that the presence of agonistic autoantibodies to angiotensin receptor type I (AT(1)-AAs) in the sera of women with preeclampsia12.Zhou C.C. Zhang Y. Irani R.A. et al.Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.Nat Med. 2008; 14: 855-862Crossref PubMed Scopus (336) Google Scholar (Figure 1). The injection of such AT(1)-AAs from preeclamptic women into pregnant mice induces the key features of preeclampsia, such as hypertension, proteinuria, glomerular endotheliosis, placental abnormalities and embryonic defects. Such symptoms in AT(1)-AA-injected pregnant mice are attenuated with losartan, an AT1 receptor antagonist, or when a neutralizing peptide against AT(1)-AAs is administered. This evidence shows that despite the suppression of PRA in preeclampsia, activation of the angiotensin receptor might be key to understanding the mechanism/s of hypertension in preeclampsia. The underlying mechanisms that drive the production of AT(1)-AAs in preeclampsia are still unknown. In the 1980s, several reports demonstrated the efficacy of an angiotensin-converting enzyme inhibitor (captopril) in preeclamptic women, with significant improvement of hypertension.13.Hurault de Ligny B.H. Ryckelynck J.P. Mintz P. et al.Captopril therapy in preeclampsia.Nephron. 1987; 46: 329-330Crossref PubMed Scopus (7) Google Scholar,14.Coen G. Cugini P. Gerlini G. et al.Successful treatment of long-lasting severe hypertension with captopril during a twin pregnancy.Nephron. 1985; 40: 498-500Crossref PubMed Scopus (15) Google Scholar These findings suggest that preeclampsia-associated hypertension may result from overactive angiotensin receptor signaling, or a vasoactive substance-induced vasoconstriction (Figure 1). Unfortunately, AT1 receptor antagonists and ACE inhibitors cannot be used in the clinic to treat women with preeclampsia because of their serious teratogenic effects. During human placental development, cytotrophoblasts differentiate into two different types of invasive trophoblasts: multinuclear syncytiotrophoblasts and extravillous trophoblasts.15.Cross J.C. Werb Z. Fisher S.J. Implantation and the placenta: key pieces of the development puzzle.Science. 1994; 266: 1508-1518Crossref PubMed Scopus (1135) Google Scholar,16.Zhou Y. Fisher S.J. Janatpour M. et al.Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?.J Clin Invest. 1997; 99: 2139-2151Crossref PubMed Scopus (770) Google Scholar Such differentiation has a pivotal role in the establishment of uteroplacental circulation, which occurs at around 12–13 weeks of gestation.17.Jauniaux E. Hempstock J. Greenwold N. et al.Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies.Am J Pathol. 2003; 162: 115-125Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar Extravillous trophoblasts subsequently invade into the uterine vasculature (endovascular invasion) and make direct contact with maternal blood.16.Zhou Y. Fisher S.J. Janatpour M. et al.Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?.J Clin Invest. 1997; 99: 2139-2151Crossref PubMed Scopus (770) Google Scholar It is speculated that such vascular remodeling through the invasion of trophoblasts including replacement of the smooth muscle layer of spiral arteries by trophoblasts, results in vessels that are resistant to vasoactive substances, thereby making such vessels independent of the control of maternal blood pressure regulation. Consequently, normal placental circulation is characterized by dilated vessels with low resistance.18.Karimu A.L. Burton G.J. The effects of maternal vascular pressure on the dimensions of the placental capillaries.Br J Obstet Gynaecol. 1994; 101: 57-63Crossref PubMed Scopus (51) Google Scholar In preeclampsia, however, such trophoblast invasion is shallow and the spiral arteries are not remodeled appropriately.19.Meekins J.W. Pijnenborg R. Hanssens M. et al.A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.Br J Obstet Gynaecol. 1994; 101: 669-674Crossref PubMed Scopus (738) Google Scholar As a result, the placental circulation does not carry sufficient blood supply to meet the embryonic demand due to these high-resistance/non-dilated vessels. Acute atherosis is another prominent vascular alteration that is often observed in preeclampsia, and also in idiopathic intrauterine growth retardation.19.Meekins J.W. Pijnenborg R. Hanssens M. et al.A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.Br J Obstet Gynaecol. 1994; 101: 669-674Crossref PubMed Scopus (738) Google Scholar,20.Zeek P.M. Assali N.S. Vascular changes in the decidua associated with eclamptogenic toxemia of pregnancy.Am J Clin Pathol. 1950; 20: 1099-1109Crossref PubMed Scopus (156) Google Scholar Such vasculopathy of the spiral arteries is defined by fibrinoid necrosis of the vessel wall, accumulation of lipid-laden macrophages, and a mononuclear perivascular infiltrate.21.Labarrere C.A. Acute atherosis. A histopathological hallmark of immune aggression?.Placenta. 1988; 9: 95-108Abstract Full Text PDF PubMed Scopus (108) Google Scholar Interestingly, similar vascular lesions have been observed in the vessels of patients with autoimmune diseases such as lupus vasculopathy,22.Sugimoto T. Kanasaki K. Morita Y. et al.Lupus vasculopathy combined with renal infarction: unusual manifestation of lupus nephritis.Intern Med. 2005; 44: 1185-1190Crossref PubMed Scopus (5) Google Scholar and in renal, cardiac, and hepatic transplant–graft rejection.21.Labarrere C.A. Acute atherosis. A histopathological hallmark of immune aggression?.Placenta. 1988; 9: 95-108Abstract Full Text PDF PubMed Scopus (108) Google Scholar Immunofluorescence analysis reveals extensive vascular deposition of non-specific IgM and complement in these lesions.23.Hustin J. Foidart J.M. Lambotte R. Maternal vascular lesions in pre-eclampsia and intrauterine growth retardation: light microscopy and immunofluorescence.Placenta. 1983; 4: 489-498PubMed Google Scholar Acute atherosis may contribute to the impairment of feto-placental circulation and efficient nutrient/gas exchange.24.Sebire N.J. Sepulveda W. Correlation of placental pathology with prenatal ultrasound findings.J Clin Pathol. 2008; 61: 1276-1284Crossref PubMed Scopus (41) Google Scholar It is not clear whether such acute atherosis is the consequence of incomplete remodeling of vessels due to shallow invasion of trophoblasts. Increased proteinuria during pregnancy is associated with poor outcome in preeclampsia. The kidney defect in preeclampsia is characterized by a distinct glomerular lesion known as ‘glomerular endotheliosis’, defined by an enlarged glomerular volume with swelling of endothelial cells and occlusion of capillary lumens. Mesangial cells of the glomeruli may also show swelling. Such changes in the endothelium are unique to preeclamptic glomeruli and are not found in the endothelium of other organs in preeclamptic women. Despite the presence of proteinuria, glomerular podocytes appear relatively normal. Furthermore, glomerular endotheliosis is not observed in the glomeruli of patients with other hypertensive disorders. Glomerular endotheliosis may contribute to the increased proteinuria and decreased glomerular filtration rate observed in preeclampsia.25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar,26.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar Recent reports have suggested that circulating angiogenic factors in the blood of preeclamptic women are responsible for the emergence of glomerular endotheliosis. Among such molecules, increased levels of soluble vascular endothelial growth factor (VEGF) type 1 receptor (also known as soluble Fms-like tyrosine kinase 1, sFlt1) is believed to contribute to the onset of glomerular endotheliosis. sFlt1 (∼100 kDa), a transcriptional variant of full-length Flt1, is a secreted protein without the transmembrane/cytoplasmic domains and serves as an endogenous inhibitor of angiogenesis. Interestingly, injection of sFlt1 protein25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar or adenoviral delivery of sFlt126.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar induces glomerular endotheliosis-like lesions in mice and rats. Such lesions are also found in mice treated with VEGF-neutralizing antibody (VEGF-Ab).25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar In addition, mice injected with VEGF-Ab and sFlt1 develop proteinuria and a decrease in podocyte expression of nephrin.25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar These findings suggest that depletion of VEGF in the glomeruli may be responsible for glomerular endotheliosis and disruption of glomerular microvascular homeostasis.25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar In this regard, a recent report identified a human-specific splicing variant of VEGF type 1 receptor (designated sFlt1-14) that is qualitatively different from the previously described soluble receptor (sFlt1) and functions as a potent VEGF inhibitor.27.Sela S. Itin A. Natanson-Yaron S. et al.A novel human-specific soluble vascular endothelial growth factor receptor 1: cell-type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia.Circ Res. 2008; 102: 1566-1574Crossref PubMed Scopus (162) Google Scholar sFlt1-14 is generated in a cell type-specific manner, primarily in nonendothelial cells such as vascular smooth muscle cells. The expression of sFlt1-14 is elevated in the placenta of women with preeclampsia, and is specifically induced in abnormal clusters of degenerative syncytiotrophoblasts known as syncytial knots. More studies are required to understand the role of sFlt1-14 in preeclampsia. Nevertheless, it is possible that the non-specific antibody detection methods to assay sFlt1 may have detected this novel human-specific isoform (sFlt1-14) along with sFlt1, in many of the previously reported studies.26.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar, 28.Levine R.J. Maynard S.E. Qian C. et al.Circulating angiogenic factors and the risk of preeclampsia.N Engl J Med. 2004; 350: 672-683Crossref PubMed Scopus (2563) Google Scholar, 29.Venkatesha S. Toporsian M. Lam C. et al.Soluble endoglin contributes to the pathogenesis of preeclampsia.Nat Med. 2006; 12: 642-649Crossref PubMed Scopus (1328) Google Scholar, 30.Levine R.J. Lam C. Qian C. et al.Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.N Engl J Med. 2006; 355: 992-1005Crossref PubMed Scopus (1343) Google Scholar Decreased blood circulation in the uteroplacental unit (possibly as a result of abnormal placentation) may partially explain the pathogenesis of preeclampsia.31.Lunell N.O. Nylund L.E. Lewander R. et al.Uteroplacental blood flow in pre-eclampsia measurements with indium-113 m and a computer-linked gamma camera.Clin Exp Hypertens B. 1982; 1: 105-117Crossref PubMed Scopus (161) Google Scholar,32.Genbacev O. Joslin R. Damsky C.H. et al.Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia.J Clin Invest. 1996; 97: 540-550Crossref PubMed Scopus (462) Google Scholar In 1939, Page showed that relative ischemia in the placenta was associated with eclampsia.33.Page E.W. The relation between hydatid moles, relative ischemia of the gravid uterus, and the placental origin of eclampsia.Am J Obstet Gynecol. 1939; 37: 291-293Google Scholar In fact, Lunell et al.31.Lunell N.O. Nylund L.E. Lewander R. et al.Uteroplacental blood flow in pre-eclampsia measurements with indium-113 m and a computer-linked gamma camera.Clin Exp Hypertens B. 1982; 1: 105-117Crossref PubMed Scopus (161) Google Scholar described a 50% decrease in uteroplacental circulation in preeclamptic women. In support of this observation Ogden et al. demonstrated in 1940 that a 50% reduction of uteroplacental circulation in dogs (by clamping the descending aorta) resulted in approximately 25 mm Hg increase in blood pressure.34.Ogden E. Hildebrand G.J. Page E.W. Rise of blood pressure during ischemia of the gravid uterus.Proc Soc Exp Biol Med. 1940; 43: 49-51Crossref Scopus (44) Google Scholar Subsequently, several animal studies have validated the association between preeclampsia-like symptoms and reduced placental perfusion.35.Roberts J.M. Lain K.Y. Recent insights into the pathogenesis of pre-eclampsia.Placenta. 2002; 23: 359-372Abstract Full Text PDF PubMed Scopus (485) Google Scholar These studies indicate that the reduction in placental circulation is likely a fundamental factor in the onset of preeclampsia. It has been hypothesized that abnormal implantation in the first trimester of pregnancy36.Redline R.W. Patterson P. Pre-eclampsia is associated with an excess of proliferative immature intermediate trophoblast.Hum Pathol. 1995; 26: 594-600Abstract Full Text PDF PubMed Scopus (172) Google Scholar and/or defects in vascular remodeling19.Meekins J.W. Pijnenborg R. Hanssens M. et al.A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.Br J Obstet Gynaecol. 1994; 101: 669-674Crossref PubMed Scopus (738) Google Scholar are major factors contributing to the reduction of placental circulation. However, the precise mechanisms leading to placental hypoxia in preeclampsia still remain unclear. How does placental hypoxia cause the maternal symptoms of preeclampsia? This important question is still an open debate. One theory is that reduced placental perfusion results in the production of numerous placenta-derived circulatory agents, which cause the maternal symptoms of preeclampsia. Among these factors, sFlt1 is speculated to be an important candidate molecule associated with the pathogenesis of preeclampsia.37.Vuorela-Vepsalainen P. Alfthan H. Orpana A. et al.Vascular endothelial growth factor is bound in amniotic fluid and maternal serum.Hum Reprod. 1999; 14: 1346-1351Crossref PubMed Scopus (47) Google Scholar, 38.Vuorela P. Helske S. Hornig C. et al.Amniotic fluid-soluble vascular endothelial growth factor receptor-1 in preeclampsia.Obstet Gynecol. 2000; 95: 353-357Crossref PubMed Scopus (109) Google Scholar, 39.Helske S. Vuorela P. Carpen O. et al.Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies.Mol Hum Reprod. 2001; 7: 205-210Crossref PubMed Scopus (184) Google Scholar, 40.Zhou Y. McMaster M. Woo K. 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.Am J Pathol. 2002; 160: 1405-1423Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar The underlying theory of how sFlt1 is involved in the pathogenesis of preeclampsia stems from research by the Finnish group, Vuorela et al.37.Vuorela-Vepsalainen P. Alfthan H. Orpana A. et al.Vascular endothelial growth factor is bound in amniotic fluid and maternal serum.Hum Reprod. 1999; 14: 1346-1351Crossref PubMed Scopus (47) Google Scholar, showing that VEGF is bound to a circulating protein in the amniotic fluid and maternal serum. In 2000, the same research group reported that sFlt1 is significantly elevated in the amniotic fluid of preeclamptic women.38.Vuorela P. Helske S. Hornig C. et al.Amniotic fluid-soluble vascular endothelial growth factor receptor-1 in preeclampsia.Obstet Gynecol. 2000; 95: 353-357Crossref PubMed Scopus (109) Google Scholar This seminal work by Vuorela et al. was the first report implicating sFlt1 in preeclampsia. Subsequently, Fisher and co-workers showed that cytotrophoblasts from preeclamptic placentae show higher levels of sFlt1 in vitro when compared with control cells from normal placentae.40.Zhou Y. McMaster M. Woo K. 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.Am J Pathol. 2002; 160: 1405-1423Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar In 2003, Sugimoto et al.25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar showed that the neutralization of VEGF with sFlt1 or anti-VEGF antibodies in mice leads to proteinuria. Later in 2003, Maynard et al.26.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar reported that the concentration of sFlt1 in the maternal serum of preeclamptic women was increased when compared with normal pregnant women, and that adenoviral delivery of sFlt1 in rats caused endotheliosis and hypertension in males, and both pregnant and non-pregnant female rats. It is speculated that excess sFlt1 neutralizes both free VEGF and free placental growth factor (PlGF) in maternal circulation, resulting in endothelial damage and the onset of the clinical syndrome.25.Sugimoto H. Hamano Y. Charytan D. et al.Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt1) induces proteinuria.J Biol Chem. 2003; 278: 12605-12608Crossref PubMed Scopus (447) Google Scholar,26.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar Although the placenta is believed to be responsible for the excess sFlt1 production in preeclampsia, this has not been explicitly shown because of the pan-specificity of the antibodies to Flt1 and sFlt1. Clinical studies have shown that sFlt1 is elevated in the blood of women with preeclampsia26.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar,28.Levine R.J. Maynard S.E. Qian C. et al.Circulating angiogenic factors and the risk of preeclampsia.N Engl J Med. 2004; 350: 672-683Crossref PubMed Scopus (2563) Google Scholar and that PlGF concentration is suppressed in the urine of women with preeclampsia.26.Maynard S.E. Min J.Y. Merchan J. et al.Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111: 649-658Crossref PubMed Scopus (2875) Google Scholar, 41.Krauss T. Pauer H.U. Augustin H.G. Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia.Hypertens Pregnancy. 2004; 23: 101-111Crossref PubMed Scopus (100) Google Scholar, 42.Levine R.J. Thadhani R. Qian C. et al.Urinary placental growth factor and risk of preeclampsia.JAMA. 2005; 293: 77-85Crossref PubMed Scopus (272) Google Scholar Interestingly, preeclampsia does not develop in all women with high sFlt1 or low PlGF levels, and furthermore, can occur in some women with low sFlt1 and high PlGF levels.28.Levine R.J. Maynard S.E. Qian C. et al.Circulating angiogenic factors and the risk of preeclampsia.N Engl J Med. 2004; 350: 672-683Crossref PubMed Scopus (2563) Google Scholar Therefore, although the involvement of placenta-derived sFlt1 in the pathogenesis of preeclampsia is still being explored, the utility of sFlt1 and PlGF levels as diagnostic biomarkers for predicting preeclampsia is independently being evaluated. In the AT(1)-AA-induced preeclampsia-like disease in mice, elevation of sFlt1 is also found and is speculated to contribute to the renal glomerular endothelial damage; however, a connection to hypertension was not found.12.Zhou C.C. Zhang Y. Irani R.A. et al.Angiotensin receptor agonistic autoantibodies induce pre-eclampsia" @default.
• W2051203706 created "2016-06-24" @default.
• W2051203706 creator A5004654560 @default.
• W2051203706 creator A5062422936 @default.
• W2051203706 date "2009-10-01" @default.
• W2051203706 modified "2023-10-06" @default.
• W2051203706 title "The biology of preeclampsia" @default.
• W2051203706 cites W1965181820 @default.
• W2051203706 cites W1966336145 @default.
• W2051203706 cites W1966706075 @default.
• W2051203706 cites W1969306696 @default.
• W2051203706 cites W1975029212 @default.
• W2051203706 cites W1984970610 @default.
• W2051203706 cites W1986059489 @default.
• W2051203706 cites W1999090873 @default.
• W2051203706 cites W2014871892 @default.
• W2051203706 cites W2015391784 @default.
• W2051203706 cites W2018480122 @default.
• W2051203706 cites W2019405633 @default.
• W2051203706 cites W2020451618 @default.
• W2051203706 cites W2026963612 @default.
• W2051203706 cites W2031044936 @default.
• W2051203706 cites W2032665278 @default.
• W2051203706 cites W2049595315 @default.
• W2051203706 cites W2051563676 @default.
• W2051203706 cites W2053451129 @default.
• W2051203706 cites W2053976090 @default.
• W2051203706 cites W2054923768 @default.
• W2051203706 cites W2060466218 @default.
• W2051203706 cites W2066278927 @default.
• W2051203706 cites W2072756039 @default.
• W2051203706 cites W2073589424 @default.
• W2051203706 cites W2074747030 @default.
• W2051203706 cites W2074915605 @default.
• W2051203706 cites W2080524314 @default.
• W2051203706 cites W2082216284 @default.
• W2051203706 cites W2082725991 @default.
• W2051203706 cites W2083150822 @default.
• W2051203706 cites W2084586130 @default.
• W2051203706 cites W2089782826 @default.
• W2051203706 cites W2092668546 @default.
• W2051203706 cites W2102277066 @default.
• W2051203706 cites W2105632053 @default.
• W2051203706 cites W2111984223 @default.
• W2051203706 cites W2136170834 @default.
• W2051203706 cites W2137433871 @default.
• W2051203706 cites W2138266742 @default.
• W2051203706 cites W2140476817 @default.
• W2051203706 cites W2143180984 @default.
• W2051203706 cites W2166938100 @default.
• W2051203706 cites W2169958477 @default.
• W2051203706 cites W2171162078 @default.
• W2051203706 cites W2171461451 @default.
• W2051203706 cites W2171930271 @default.
• W2051203706 cites W2312892716 @default.
• W2051203706 cites W2326184555 @default.
• W2051203706 cites W2327468680 @default.
• W2051203706 cites W4236182870 @default.
• W2051203706 cites W4251118184 @default.
• W2051203706 cites W4382916220 @default.
• W2051203706 doi "https://doi.org/10.1038/ki.2009.284" @default.
• W2051203706 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4313558" @default.
• W2051203706 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19657323" @default.
• W2051203706 hasPublicationYear "2009" @default.
• W2051203706 type Work @default.
• W2051203706 sameAs 2051203706 @default.
• W2051203706 citedByCount "139" @default.
• W2051203706 countsByYear W20512037062012 @default.
• W2051203706 countsByYear W20512037062013 @default.
• W2051203706 countsByYear W20512037062014 @default.
• W2051203706 countsByYear W20512037062015 @default.
• W2051203706 countsByYear W20512037062016 @default.
• W2051203706 countsByYear W20512037062017 @default.
• W2051203706 countsByYear W20512037062018 @default.
• W2051203706 countsByYear W20512037062019 @default.
• W2051203706 countsByYear W20512037062020 @default.
• W2051203706 countsByYear W20512037062021 @default.
• W2051203706 countsByYear W20512037062022 @default.
• W2051203706 countsByYear W20512037062023 @default.
• W2051203706 crossrefType "journal-article" @default.
• W2051203706 hasAuthorship W2051203706A5004654560 @default.
• W2051203706 hasAuthorship W2051203706A5062422936 @default.
• W2051203706 hasBestOaLocation W20512037061 @default.
• W2051203706 hasConcept C126322002 @default.
• W2051203706 hasConcept C2777218350 @default.
• W2051203706 hasConcept C2779234561 @default.
• W2051203706 hasConcept C54355233 @default.
• W2051203706 hasConcept C70721500 @default.
• W2051203706 hasConcept C71924100 @default.
• W2051203706 hasConcept C86803240 @default.
• W2051203706 hasConceptScore W2051203706C126322002 @default.
• W2051203706 hasConceptScore W2051203706C2777218350 @default.
• W2051203706 hasConceptScore W2051203706C2779234561 @default.
• W2051203706 hasConceptScore W2051203706C54355233 @default.
• W2051203706 hasConceptScore W2051203706C70721500 @default.
• W2051203706 hasConceptScore W2051203706C71924100 @default.
• W2051203706 hasConceptScore W2051203706C86803240 @default.
• W2051203706 hasIssue "8" @default.

• next