Linking Placental Ischemia and Hypertension in Preeclampsia
2012; Lippincott Williams & Wilkins; Volume: 60; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.112.194845
ISSN1524-4563
AutoresEric M. George, Joey P. Granger,
Tópico(s)Maternal and fetal healthcare
ResumoHomeHypertensionVol. 60, No. 2Linking Placental Ischemia and Hypertension in Preeclampsia Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLinking Placental Ischemia and Hypertension in PreeclampsiaRole of Endothelin 1 Eric M. George and Joey P. Granger Eric M. GeorgeEric M. George From the Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular Research, University of Mississippi Medical Center, 2500 N State St, Jackson, MS. and Joey P. GrangerJoey P. Granger From the Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular Research, University of Mississippi Medical Center, 2500 N State St, Jackson, MS. Originally published7 May 2012https://doi.org/10.1161/HYPERTENSIONAHA.112.194845Hypertension. 2012;60:507–511Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 IntroductionOne of the most pervasive disorders of pregnancy is preeclampsia, which is defined as new-onset hypertension presenting after the 20th week of gestation and is accompanied by increasing levels of proteinuria and often edema.1 The overall prevalence of preeclampsia is ≈8% with higher incidence in specific ethnic subpopulations, notably blacks.2,3 The disorder is predominantly a complication of primiparous women, who have a 3-fold higher incidence rate than multiparous women. There are a number of known factors that convey elevated risk of developing preeclampsia, notably elevated body mass index, and a previous incidence of preeclampsia, because women who experienced preeclampsia in previous pregnancies are 7 times more likely to exhibit preeclamptic symptoms in subsequent pregnancies than those with no history of preeclampsia.4 It has also been shown that high body mass index can double the risk of preeclampsia, and the scale of obesity correlates directly with the increase risk of developing the disorder.5 Although the link between these risk factors seem logical, there are also a number of other risk factors (maternal age, induced abortions, interpregnancy interval, and socioeconomic factors) for which the links to preeclampsia are not as clear.6 More research is warranted into the mechanistic effect of these factors in the etiology of preeclampsia.There are currently no definitive treatment options for the resolution of preeclampsia. Available interventions are confined to magnesium sulfate for the prophylaxis of seizures and the administration of one of various antihypertensive agents, although normalization of blood pressure is not normally possible, and the disease continues to progress.1 Indeed, the only effective resolution of preeclampsia is delivery of the placenta, because delivery of the fetus alone is not sufficient.7,8 It is this fact that suggested the pathological origins of the development of preeclampsia. Although the underlying molecular mechanisms that lie at the root of preeclampsia are not clear, it is believed that a major causative agent is placental insufficiency resulting from inadequate remodeling of the maternal vasculature.9 During normal pregnancy, fetally derived cytotrophoblasts invade the maternal spiral arteries of the uterus, replace the maternal endothelium, and undergo differentiation into an endothelial-like phenotype. This causes a conversion of the high-resistance, small-diameter vessels into high-capacitance, low-resistance vessels and ensures adequate delivery of maternal blood to the developing uteroplacental unit.7,10 In the preeclamptic patient, unknown errors in this carefully orchestrated scheme lead to inadequate delivery of blood to the developing uteroplacental unit and create hypoxia and chronic ischemia within the placenta.11 In response, the placenta produces pathogenic factors that enter the maternal bloodstream and are responsible for the clinical manifestations of the disorder. Among the factors known to be released, antiangiogenic and autoimmune/inflammatory factors have received a great deal of attention. Interestingly, recent evidence suggests that these agents have a final common pathway, activation of the endothelin 1 (ET-1) system.There are several lines of evidence that suggest a pathogenic role for ET-1 in the preeclamptic patient. A number of studies looking at circulating levels of ET-1 in preeclamptic women have generally demonstrated significantly higher levels of circulating ET-1 in the plasma of preeclamptic patients when compared with healthy controls, with some suggestion that a genetic polymorphism could play a role in the variation of ET-1 levels.12–16 However, circulating levels of ET-1 are not necessarily good indicators of ET-1 production in the tissues because of the fact that ET-1 secretion is directional, with a larger proportion of the peptide being released on the basolateral side of the endothelium, and tissue levels may not be accurately reflected in the levels of ET-1 in the circulation. Studies indicating elevations in ET-1 in preeclamptic placental cells are perhaps more telling, although this is not a universal finding.17,18 Finally, one report has indicated an increase in endothelin-converting enzyme in the circulation of preeclamptic patients compared with normal pregnant controls, suggesting a potential mechanism for enhanced local production of ET-1.19 These data support earlier studies demonstrating increased endothelin-converting enzyme production by endothelial cells exposed to preeclamptic serum.20 There are also indications that matrix metalloproteinase 2, which can also cleave big endothelin into ET-1, is significantly elevated in preeclamptic women.21,22 These findings suggest at least a correlation between ET-1 and preeclampsia in humans and warrant further study.Because studies on pregnant women are, at best, complicated, a number of experimental animal models have been used to examine the etiology and development of preeclampsia. One that we and others have used with great success is the reduced uterine perfusion pressure (RUPP) model, which mechanically restricts blood flow to the placenta, leading to hypoxia and ischemia. This model has been used in species ranging from rats to nonhuman primates and mimics a number of the pathological features of human preeclampsia, including hypertension, angiogenic imbalance, renal injury, proteinuria, and endothelial dysfunction.23–25 In studies where human endothelial cells were exposed to serum from RUPP rats in vitro, it was shown that RUPP sera significantly induced production of ET-1 from the endothelial cells when compared with those exposed to serum from normal pregnant animals, suggesting that circulating factors produced by placental ischemia are responsible for increased vascular ET-1 production.26 Initial in vivo studies suggested that both the renal cortex and medulla of RUPP rats express significantly higher levels of the ET-1 precursor, preproendothelin, at the mRNA level when compared with normal pregnant controls (Figure 1B and 1C). Crucially, when an endothelin A (ETA) receptor antagonist was administered to the RUPP rats, the associated hypertension was abolished (Figure 1A), and there was a trend for increased renal function.27 These studies suggest that placental ischemia induces factors that activate the production of ET-1 in the vasculature, which acts through ETA receptors to mediate the hypertension seen in this model. Whether similar ETA antagonism could prove effective in preeclamptic women remains to be seen.Download figureDownload PowerPointFigure 1. Effect of endothelin A (ETA) antagonism on reduced uterine perfusion pressure (RUPP)–induced hypertension. As seen in A, RUPP-treated animals exhibit significant hypertension when compared with normal pregnant controls. This hypertensive response is completely blocked by administration of an ETA selective antagonist. In both the renal cortex (B) and medulla (C), RUPP treatment significantly increases the expression of preproendothelin relative to β-actin mRNA as determined by RNase protection assays. (*P<0.05). Adapted from Alexander et al.27Soluble Fms-Like Tyrosine Kinase 1One of the most intensely studied pathways in the manifestation of preeclampsia is the vascular endothelial growth factor (VEGF) signaling pathway. VEGF, other than its role in angiogenesis, has an important role in the maintenance of proper endothelial cell function and health. This signaling pathway came to prominence with the discovery of elevated circulating and placental levels of the soluble form of the VEGF receptor, Flt-1, denominated soluble Fms-like tyrosine kinase 1 (sFlt-1).28,29 sFlt-1 acts as a direct inhibitor of VEGF by binding to the protein and preventing it from being available for its normal function.30 Subsequent studies looking at the regulation of sFlt-1 in cell culture and placental tissue in vitro have demonstrated that sFlt-1 is released from placental villi and trophoblast cells in response to reduced oxygen tensions similar to that seen in the ischemic placenta.31–33 A promising recent pilot study demonstrated that sFlt-1 could be removed from the maternal circulation by apheresis safely and that this therapy reduced both blood pressure and proteinuria, with a trend toward increased gestational duration.34A number of groups have also reported that artificial elevation of sFlt-1 in animal models, either by direct infusion or by viral overexpression, leads to hypertension, renal injury, and proteinuria, all symptomatic of preeclampsia.29,35–41 These results are supported by clinical data showing that patients receiving the anti-VEGF antibody therapy Bevacizumab, which functions in much the same way as sFlt-1, exhibit marked proteinuria and hypertension.42 Kappers et al43 also reported that Sunitinib, a tyrosine kinase inhibitor which targets the VEGF receptor, induces a reversible rise in BP in patients and in rats associated with activation of the ET-1 system and generalized microvascular dysfunction. Finally, the same group recently reported that VEGF inhibition with Sunitinib in pigs results in endothelin-mediated hypertension in pigs.44 This suggests that another potential mechanism whereby VEGF blockade could increase BP is by enhancing ET-1 synthesis.Several reports have been made into the role of the ET-1 system in models of sFlt-1 overexpression in pregnancy.29,35,36 In support of ET-1 as a mediator of sFlt-1–induced hypertension, our group has reported recently that continuous infusion of sFlt-1 in pregnant rats directly increased the level of ET-1 in the renal cortex and resulted in an increase in the mean arterial pressure of ≈20 mmHg (Figure 2). Tellingly, with coadministration of an ETA receptor antagonist, the hypertension associated with this model was completely abolished, strongly supporting ET-1 as an important mediator of sFlt-1–induced hypertension.36Download figureDownload PowerPointFigure 2. Soluble Fms-like tyrosine kinase 1 (sFlt-1) induces hypertension through endothelin 1 (ET-1) induction. Infusion of sFlt-1 significantly increases mean arterial pressure (MAP) in pregnant rats. This hypertensive response is completely blunted with administration of an endothelin A (ETA)-selective antagonist (A). Production of preproendothelin mRNA is significantly increased in the renal cortex by sFlt-1 infusion (B). *P<0.05 vs controls; #P<0.05 vs sFlt-1–infused rats. Adapted from Murphy et al.36Autoimmune FactorsOne of the earliest and most persistent theories about the origins of preeclampsia view it as a disorder of immunity. In fact, there is a growing realization that autoimmunity plays a pivotal role in the symptomatic phase of the disorder and perhaps the early etiology of the disease as well.45–47 The autoimmune components of preeclampsia can be compartmentalized into 2 headings, the production of autoantibodies and the innate immune response. In the first category, much attention has been focused on the production of agonistic angiotensin II type 1 receptor autoantibodies (AT1-AAs), which have been found in the circulation of women with preeclampsia and verified in several experimental models. Even more clearly characterized is the innate inflammatory response mediated by inflammatory cytokines. The importance of these 2 components has begun to be elucidated, and several experimental approaches have been used to understand their role in the development of preeclampsia.One well-characterized component of the innate immune response to preeclampsia is the production of tumor necrosis factor-α (TNF-α), which is elevated in both preeclamptic women and rodents undergoing chronic placental ischemia.48–50 Previous studies in vitro demonstrated that production of ET-1 by endothelial cells could be driven by exposure to TNF-α.51 Studies from our group have demonstrated that administration of the soluble TNF-α receptor Etanercept is capable of attenuating the hypertension associated with placental ischemia in pregnant rats. This treatment is associated with reduced expression of the preproendothelin in the renal cortex and medulla, as well as the placenta itself.50 It has also been shown that infusion of TNF-α directly induced hypertension in pregnant rats, producing an ≈20-mmHg increase in mean arterial pressure in late gestation. This is associated with a significant increase in the expression of preproendothelin in the maternal vasculature, placenta, and kidney. As in the RUPP model, coadministration of an ETA receptor antagonist in these animals completely abolished the associated hypertension (Figure 3).52 Together, these data suggest that TNF-α is an important component of the hypertensive response to placental ischemia and that ET-1, acting through the ETA receptor, is a crucial mediator of TNF-α–induced hypertension.Download figureDownload PowerPointFigure 3. Tumor necrosis factor (TNF)-α induces hypertension through endothelin 1 (ET-1) induction. Infusion of TNF-α significantly increases mean arterial pressure (MAP) in pregnant rats. This hypertensive response is completely blunted with administration of an endothelin A (ETA)–selective antagonist. *P<0.05 vs controls, #P<0.05 vs TNF-α–infused rats. Adapted from LaMarca et al.52A relatively recent addition to the immune component of preeclampsia is the agonistic AT1-AAs. These antibodies were originally isolated just over a decade ago in preeclamptic women and have since been found in the circulation of rats undergoing placental ischemia.53,54 Interestingly, these antibodies appear to be induced by the production of TNF-α, because infusion of TNF-α to pregnant rats also results in production of the antibody at levels comparable to those seen in pregnant women and the RUPP rat.54 It has also been demonstrated that infusion of the AT1-AAs directly into pregnant rats results in moderate hypertension that is associated with increased preproendothelin expression in both the renal cortex and placenta. Again, administration of an ETA receptor antagonist abrogated the hypertensive response to the AT1-AA, suggesting its importance in the manifestation of AT1-AA–induced hypertension (Figure 4).55 However, the pathogenic importance of these antibodies remains to be fully elucidated, because their presence has been noted postpartum in a subset of preeclamptic patients with no discernible phenotype.56,57 It is likely, then, that these antibodies act more as modulators of the hypertensive phenotype begun by other pathogenic factors rather than as first-cause agents directly, possibly by enhancing the response of the ET-1 system. Further studies are needed to determine how these antibodies interact with the other pathogenic agents in preeclampsia to produce the clinical phenotype.Download figureDownload PowerPointFigure 4. Angiotensin II type 1 receptor autoantibody (AT1-AA) induces hypertension through endothelin 1 (ET-1) induction. Infusion of AT1-AA significantly increases mean arterial pressure (MAP) in pregnant rats, an effect that is blocked by an endothelin A (ETA)–selective antagonist. *P<0.05 vs controls, #P<0.05 vs AT1-AA–infused rats. Reprinted from LaMarca et al55 with permission of the publisher. Copyright © 2009, American Heart Association, Inc.PerspectivesGiven the myriad of experimental models of preeclampsia (placental ischemia, sFlt-1 infusion, TNF-α infusion, and AT1-AA infusion), which have proven susceptible to ETA antagonism, could the ET-1 system be a therapeutic approach in managing the hypertension associated with preeclampsia? Excitement at this approach has been tempered by work showing that genetic knockout of the ETA receptor leads to birth defects and eventual embryonic lethality in mice.58 As a result, administration of endothelin receptor antagonists is contraindicated in pregnancy.59 However, studies that have examined pharmacological antagonism of the ETA receptor during pregnancy in rats have identified specific windows of development in early and midgestation in which the agents caused phenotypes similar to that seen in the knockout. Administration of the ETA antagonist only during late gestation was not performed, and it is entirely possible that ETA receptor antagonists might prove safe and efficacious in later pregnancy, when the symptoms of preeclampsia are most severe.60 We have also demonstrated recently that induction of heme oxygenase 1 in both placental ischemia and sFlt-1–induced hypertension significantly blunts blood pressure, in part by reducing vascular production of preproendothelin 1, suggesting another mechanism through which the ET-1 system could be targeted for the management of preeclampsia (Figure 5).61,62 Alternatively, development of ETA receptor antagonists that do not cross the placental barrier would circumvent these problems altogether. Further work to determine the transmission of existing agents, as well as the development of new antagonists, could provide a truly effective therapy for the management of hypertension in the preeclamptic patient.Download figureDownload PowerPointFigure 5. Heme oxygenase 1 (HO-1) induction blocks reduced uterine perfusion pressure (RUPP)–induced hypertension. RUPP-treated rats exhibit significant elevations in mean arterial pressure (MAP) when compared with normal pregnant controls. This hypertensive response is significantly attenuated by systemic induction of HO-1, which acts in part by reduction of vascular endothelin 1 (ET-1). *P<0.05 vs normal controls, #P<0.05 vs RUPP animals. Adapted from George et al.61Sources of FundingThis work was supported by National Institutes of Health grants HL51971, HL108618–01, and 1T32HL105324–01 and a postdoctoral fellowship from the American Heart Association (11POST7840039).DisclosuresNone.FootnotesThis paper was sent to Robert M. Carey, Consulting editor, for review by expert referees, editorial decision, and final disposition.Correspondence to Joey P. Granger, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. E-mail [email protected]eduReferences1. Turner JA. Diagnosis and management of pre-eclampsia: an update. Int J Womens Health. 2010; 2:327–337.CrossrefMedlineGoogle Scholar2. Roberts JM, Pearson G, Cutler J, Lindheimer M. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension. 2003; 41:437–445.LinkGoogle Scholar3. Knuist M, Bonsel GJ, Zondervan HA, Treffers PE. Risk factors for preeclampsia in nulliparous women in distinct ethnic groups: a prospective cohort study. Obstet Gynecol. 1998; 92:174–178.MedlineGoogle Scholar4. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005; 330:565.CrossrefMedlineGoogle Scholar5. Gaillard R, Steegers EA, Hofman A, Jaddoe VW. Associations of maternal obesity with blood pressure and the risks of gestational hypertensive disorders: the Generation R Study. J Hypertens. 2011; 29:937–944.CrossrefMedlineGoogle Scholar6. Trogstad L, Magnus P, Stoltenberg C. Pre-eclampsia: risk factors and causal models. Best Pract Res Clin Obstet Gynaecol. 2011; 25:329–342.CrossrefMedlineGoogle Scholar7. Hladunewich M, Karumanchi SA, Lafayette R. Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol. 2007; 2:543–549.CrossrefMedlineGoogle Scholar8. Shembrey MA, Noble AD. An instructive case of abdominal pregnancy. Aust NZ J Obstet Gynaecol. 1995; 35:220–221.CrossrefMedlineGoogle Scholar9. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972; 1:177–191.MedlineGoogle Scholar10. Khong Y, Brosens I. Defective deep placentation. Best Pract Res Clin Obstet Gynaecol. 2011; 25:301–311.CrossrefMedlineGoogle Scholar11. Rajakumar A, Doty K, Daftary A, Harger G, Conrad KP. Impaired oxygen-dependent reduction of HIF-1α and -2α proteins in pre-eclamptic placentae. Placenta. 2003; 24:199–208.CrossrefMedlineGoogle Scholar12. Taylor RN, Varma M, Teng NN, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab. 1990; 71:1675–1677.CrossrefMedlineGoogle Scholar13. Baksu B, Davas I, Baksu A, Akyol A, Gulbaba G. Plasma nitric oxide, endothelin-1 and urinary nitric oxide and cyclic guanosine monophosphate levels in hypertensive pregnant women. Int J Gynaecol Obstet. 2005; 90:112–117.CrossrefMedlineGoogle Scholar14. Nishikawa S, Miyamoto A, Yamamoto H, Ohshika H, Kudo R. The relationship between serum nitrate and endothelin-1 concentrations in preeclampsia. Life Sci. 2000; 67:1447–1454.CrossrefMedlineGoogle Scholar15. Maltaris T, Scalera F, Schlembach D, Hoffmann I, Mueller A, Binder H, Goecke T, Hothorn T, Schild RL, Beckmann MW, Dittrich R. Increased uterine arterial pressure and contractility of perfused swine uterus after treatment with serum from pre-eclamptic women and endothelin-1. Clin Sci (Lond). 2005; 109:209–215.CrossrefMedlineGoogle Scholar16. Aggarwal PK, Jain V, Srinivasan R, Jha V. Maternal EDN1 G5665T polymorphism influences circulating endothelin-1 levels and plays a role in determination of preeclampsia phenotype. J Hypertens. 2009; 27:2044–2050.CrossrefMedlineGoogle Scholar17. Faxen M, Nasiell J, Lunell NO, Blanck A. Differences in mRNA expression of endothelin-1, c-fos and c-jun in placentas from normal pregnancies and pregnancies complicated with preeclampsia and/or intrauterine growth retardation. Gynecol Obstet Invest. 1997; 44:93–96.CrossrefMedlineGoogle Scholar18. Napolitano M, Miceli F, Calce A, Vacca A, Gulino A, Apa R, Lanzone A. Expression and relationship between endothelin-1 messenger ribonucleic acid (mRNA) and inducible/endothelial nitric oxide synthase mRNA isoforms from normal and preeclamptic placentas. J Clin Endocrinol Metab. 2000; 85:2318–2323.CrossrefMedlineGoogle Scholar19. Ajne G, Wolff K, Fyhrquist F, Carlstrom K, Hemsen-Mortberg A, Nisell H. Endothelin converting enzyme (ECE) activity in normal pregnancy and preeclampsia. Hypertens Pregnancy. 2003; 22:215–224.CrossrefMedlineGoogle Scholar20. Nishikawa S, Miyamoto A, Yamamoto H, Ohshika H, Kudo R. Preeclamptic serum enhances endothelin-converting enzyme expression in cultured endothelial cells. Am J Hypertens. 2001; 14:77–83.CrossrefMedlineGoogle Scholar21. Narumiya H, Zhang Y, Fernandez-Patron C, Guilbert LJ, Davidge ST. Matrix metalloproteinase-2 is elevated in the plasma of women with preeclampsia. Hypertens Pregnancy. 2001; 20:185–194.CrossrefMedlineGoogle Scholar22. Myers JE, Merchant SJ, Macleod M, Mires GJ, Baker PN, Davidge ST. MMP-2 levels are elevated in the plasma of women who subsequently develop preeclampsia. Hypertens Pregnancy. 2005; 24:103–115.CrossrefMedlineGoogle Scholar23. Alexander BT, Kassab SE, Miller MT, Abram SR, Reckelhoff JF, Bennett WA, Granger JP. Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide. Hypertension. 2001; 37:1191–1195.LinkGoogle Scholar24. Abitbol MM, Ober MB, Gallo GR, Driscoll SG, Pirani CL. Experimental toxemia of pregnancy in the monkey, with a preliminary report on renin and aldosterone. Am J Pathol. 1977; 86:573–590.MedlineGoogle Scholar25. Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R, Waugh R, McKenzie P, Kirwan P, Hennessy A. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int. 2007; 71:977–984.CrossrefMedlineGoogle Scholar26. Roberts L, LaMarca BB, Fournier L, Bain J, Cockrell K, Granger JP. Enhanced endothelin synthesis by endothelial cells exposed to sera from pregnant rats with decreased uterine perfusion. Hypertension. 2006; 47:615–618.LinkGoogle Scholar27. Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA, Granger JP. Endothelin type a receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension. 2001; 37:485–489.LinkGoogle Scholar28. Signore C, Mills JL, Qian C, Yu K, Lam C, Epstein FH, Karumanchi SA, Levine RJ. Circulating angiogenic factors and placental abruption. Obstet Gynecol. 2006; 108:338–344.CrossrefMedlineGoogle Scholar29. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111:649–658.CrossrefMedlineGoogle Scholar30. Wu FT, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med. 2010; 14:528–552.MedlineGoogle Scholar31. Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res. 2004; 95:884–891.LinkGoogle Scholar32. Nagamatsu T, Fujii T, Kusumi M, Zou L, Yamashita T, Osuga Y, Momoeda M, Kozuma S, Taketani Y. Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology. 2004; 145:4838–4845.CrossrefMedlineGoogle Scholar33. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A, Zamudio S, Caniggia I. Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol. 2006; 291:R1085–R1093.CrossrefMedlineGoogle Scholar34. Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, Jank A, Kribs A, Cornely OA, Kreyssig C, Hemphill L, Rigby AC, Khedkar S, Lindner TH, Mallmann P, Stepan H, Karumanchi SA, Benzing T. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011; 124:940–950.LinkGoogle Scholar35. Bridges JP, Gilbert JS, Colson D, Gilbert SA, Dukes MP, Ryan MJ, Granger JP. Oxidative stress contributes to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats. Am J Hypertens. 2009; 22:564–568.CrossrefMedlineGoogle Scholar36. Murphy SR, LaMarca BB, Cockrell K, Granger JP. Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats. Hypertension. 2010; 55:394–398.LinkGoogle Scholar37. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A, O'Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA, Pollitt NS. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007; 50:686–692.LinkGoogle Scholar38. Suzuki H, Ohkuchi A, Matsubara S, Takei Y, Murakami M, Shibuya M, Suzuki M, Sato Y. Effect of recombinant placental growth factor 2 on hypertension induced by full-length mouse soluble fms-like tyrosine kinase 1 adenoviral vector in pregnant mice. Hypertension. 2009; 54:1129–1135.LinkGoogle Scholar39. Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W, Christofori G, Gross V, da Costa Gonzalves AC, Grone HJ, Ahmed A, Weich HA. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J Cell Mol Med. 2009.CrossrefMedlineGoogle Scholar40. Gilbert JS, Verzwyvelt J, Colson D, Arany M, Karumanchi SA, Granger JP. Recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with placentalischemia-induced hypertension. Hypertension. 2010; 55:380–385.LinkGoogle Scholar41. Sunderland N, Hennessy A, Makris A. Animal models of pre-eclampsia. Am J Reprod Immunol. 2011; 65:533–541.CrossrefMedlineGoogle Scholar42. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007; 49:186–193.CrossrefMedlineGoogle Scholar43. Kappers MH, Smedts FM, Horn T, van Esch JH, Sleijfer S, Leijten F, Wesseling S, Strevens H, Jan Danser AH, van den Meiracker AH. The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. Hypertension. 2011; 58:295–302.LinkGoogle Scholar44. Kappers MH, de Beer VJ, Zhou Z, Danser AH, Sleijfer S, Duncker DJ, van den Meiracker AH, Merkus D. Sunitinib-induced systemic vasoconstriction in swine is endothelin mediated and does not involve nitric oxide or oxidative stress. Hypertension. 2012; 59:151–157.LinkGoogle Scholar45. Xia Y, Kellems RE. Is preeclampsia an autoimmune disease?Clin Immunol. 2009; 133:1–12.CrossrefMedlineGoogl
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