Defective Uteroplacental Vascular Remodeling in Preeclampsia: Comparison
Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Hee Jin Park.

Preeclampsia is a subtype of hypertensive disorders of pregnancy (HDP), defined as hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) newly developed at or after 20 weeks of pregnancy with at least one of following conditions: proteinuria (≥1 + dipstick; ≥30 mg/mmol protein:creatinine ratio; or ≥300 mg/24 h), maternal organ dysfunction (hepatic, renal, hematological, or neurological conditions), or uteroplacental dysfunction (such as abnormal umbilical artery Doppler wave form analysis, fetal growth restriction, or stillbirth)

  • preeclampsia
  • cardiovascular disease

1. Uteroplacental Vascular Development in Normal Pregnancy

The development of placental vasculature begins from the beginning of pregnancy as the blastocyst implants into the decidua. The cytotrophoblasts which originate from the extra-embryonic membranes of the fertilized ovum mediate this process by differentiating into endothelial cells as they invade into the uterine wall to form primary capillaries of placental vasculature [5][1]. As the implanted embryo develops, trophoblast cells continue to branch into the inner third of the myometrium and reach the maternal spiral arteries at the intervillous space where maternal-placental circulation occurs. Uterine spiral arteries are nonbranching end arteries of uterine arteries which penetrate the inner part of the myometrium and the endometrium with a corkscrew shape [6][2]. During pregnancy, the spiral arteries are responsible for providing adequate perfusion of uteroplacental blood flow. Therefore, the spiral arteries are physiologically modified in order to change from high-resistance vessels to dilated low-resistance vessels with a thin wall [7][3]. The process of so-called “spiral artery remodeling” has been suggested to have five stages according to Pijenborg et al. [8][4]. Stage 1 involves the swelling of individual smooth muscle cell in the uterine spiral artery along with endothelial vacuolation. Stage 2 begins with interstitial trophoblasts invading the perivascular tissues and disorganizing the vascular smooth muscle layer. It is followed by the appearance of endovascular trophoblasts (stage 3) and the trophoblast becomes embedded into the vessel wall, becoming intramural trophoblasts in stage 4. In stage 5, the re-endothelialization with newly built endothelium and the thickening of subintima containing myofibroblasts occur. During the process, several regulatory factors are involved; the high oxygen concentration in the spiral artery initiates the endovascular trophoblast invasion and activation of maternal decidual natural killer cells and platelets enhance their invasion [9][5]. Therefore, eventually the spiral arteries are physiologically altered to exhibit low vascular resistance and enhanced vasodilation, and this is specifically designed to provide sufficient uteroplacental circulation, which is critical for a successful pregnancy.

2. Defective Uteroplacental Vascular Remodeling in Preeclampsia

The association with failed spiral artery remodeling in development of preeclampsia was first brought up in 1972 by Brosens et al. [7][3]. Subsequent studies have revealed that due to a failure in the process of endovascular trophoblast invasions, spiral arteries fail to go through the physiological alteration process which results in relatively narrow, thick-walled and tortuous vessels in preeclampsia. Moreover, unlike in a normal pregnancy in which the transformation of the spiral artery extends from the decidual segment to one-third of the myometrial segment, in preeclampsia trophoblasts fail to invade into the myometrial segment of spiral arteries [10][6]. As a consequence, deep placentation fails and the blood flow to the placenta is restricted leading to inadequate uteroplacental perfusion. This phenomenon is found in various adverse pregnancy outcomes along with preeclampsia, such as fetal growth restriction, placental abruption, preterm labor, preterm premature rupture of membranes, and intrauterine fetal death [11,12,13,14][7][8][9][10].

3. Molecular Factors Resulting from Inadequate Uteroplacental Perfusion Leading to Preeclampsia

3.1. Inflammatory Factors

Placental ischemia due to reduced uteroplacental perfusion pressure (RUPP) increases the release of proinflammatory cytokines. TNF-α is increased in plasma of women with preeclampsia as compared to normal pregnant women [28][11], which increases vascular permeability and lymphocyte activation and disrupts mitochondrial function leading to oxidative stress [29][12].
Interleukin-6 (IL-6) is elevated in patients with preeclampsia compared to women with normal pregnancy [28][11]. IL-6 dislocates the tight junctions in endothelial cells which leads to increased vascular permeability and endothelial dysfunction [30][13]. This has been confirmed in rats with reduced uteroplacental perfusion which showed increased plasma levels of IL-6 with high CD4+ T cell production of inflammatory cytokines [31][14]. Also, chronic infusion of IL-6 in pregnant rats caused hypertension and proteinuria along with reduced vascular relaxation [32][15].
Interleukin-10 (IL-10) is an anti-inflammatory cytokine which is reduced in the placenta of rats with reduced uteroplacental perfusion and in serum of women with preeclampsia [33,34][16][17]. A recent meta-analysis of 56 studies on the circulating IL-10 levels in preeclamptic women revealed that the serum IL-10 levels were not significantly different before the onset of preeclampsia; however, once the clinical syndrome of preeclampsia occurs, IL-10 levels were significantly lower in preeclamptic women compared to normotensive controls (standardized mean differences, −0.79 [95% CI, −1.22 to −0.35]; p = 0.0004). Moreover, the decreased level of IL-10 was present in all forms of preeclampsia regardless of its onset and severity [35][18]. This suggests that IL-10 levels may not be a suitable marker for early detection of preeclampsia, but increasing IL-10 may be a potential therapeutic target of preeclampsia, which could lead to future studies.

3.2. Reactive Oxygen Species (ROS)

Reactive Oxygen Species (ROS) such as superoxide, hydrogen peroxide, and the hydroxyl ion contains highly reactive oxygen. Pregnancy itself is a state of oxidative stress resulting from placental metabolism and increased maternal metabolic activity, which is counterbalanced by abundant antioxidants [36][19]. In preeclampsia, decreased expression of antioxidants such as heme oxygenase-1 (HO-1), HO-2, copper/zinc superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase fails to counterbalance the increased ROS production, leading to lipid peroxidation, increased thromboxane A2 and loss of GPx activity in the placenta [37][20]. The impaired blood flow in the spiral arteries due to RUPP also mediates an ischemia/hypoxia-reperfusion injury, leading to oxidative changes in placental proteins and lipids, mitochondrial injury, and increased ROS production [38][21]. In women with preeclampsia, decreased serum levels of the antioxidant ascorbate were shown to be associated with decreased brachial artery flow-mediated dilation, and administration of ascorbic acid improved flow mediated dilation, supporting an association between endothelial dysfunction and oxidative stress in preeclampsia [39][22].
Moreover, oxidative stress results in reduced bioavailability of nitric oxide (NO), a major vasodilator which regulates blood pressure in placenta [40][23]. Oxidative stress inhibits nitric oxide synthase (eNOS) which is required for biosynthesis of NO, and the radical anion superoxide (O2•−) reacts with NO to form peroxynitrite (ONOO), which is a strong pro-inflammatory factor [41][24].

3.3. Angiotensin II (AngII) and Angiotensin II Type 1 Receptor (AT1R) Autoantibodies (AT1-AA)

Angiotensin II (AngII) is an important regulator of blood pressure and electrolyte homeostasis. About 40% of AngII is produced locally in the placenta by chymase, a chymotrypsin-like serine protease, which is a non-angiotensin converting enzyme found mainly in the syncytiotrophoblast of the placenta. AngII via the AngII type 1 receptor (AT1R) promotes vasoconstriction, vascular growth, and inflammation, and increases intracellular free Ca2+ concentration and Rho/Rho-kinase activity in vascular smooth muscle. AngII via the endothelial angiotensin II type 2 receptor (AT2R) activates eNOS, and increases production of NO and prostacyclin (PGI2) which oppose AngII-induced vasoconstriction. Although increased plasma levels of renin and AngII is observed in normal pregnancy, the response to AngII is decreased due to decreased expression of AT1R, possibly by AT2R. However, hypoxia in RUPP has been shown to increase the AT1R expression and plasma levels of AngII in rabbits, as well as in human preeclamptic placentas [42,43][25][26].
In preeclampsia, AT1R forms a heterodimer with the bradykinin B2 receptor (B2R) called AT1R-B2R protein complex and becomes hyper-responsive to AngII; AT1R-B2R formation is increased in preeclampsia since down-regulation of the protein complex expression is inhibited due to beta-arrestin1 (ARRB1) dysfunction [44][27]. Therefore, AT1R-B2R has become an emerging treatment target of preeclampsia. The beta-arrestin-biased AT1R agonist, TRV027, is expected to stimulate the AT1R-B2R downregulation—which is impaired in preeclampsia—and recent experiments have shown that it actually lowered blood pressure and prevented symptoms of preeclampsia in animal models [44,45][27][28].
AT1-AA are agonistic autoantibodies to the AT1R that mediates vascular signaling via protein-1, calcineurin, and nuclear factor kappa B (NFκB). AT1-AA induces the secretion of plasminogen activator inhibitor-1 (PAI-1) which inhibits trophoblast invasion, increases ROS, increases intracellular free Ca2+ concentration, activates the tissue factor causing thrombosis, and increases blood pressure [46][29]. Moreover, AT1-AA along with circulating cytokines stimulate endothelial cells to produce endothelin-1 (ET-1) in preeclampsia, which is a major endothelium-derived vasoconstrictor [47][30]. Infusion of CD4+ T cells obtained from preeclamptic women in pregnant rats stimulates the immunoglobulin release from B-cells which in turn increases AT1-AA production while inhibition of B-cells reduces AT1-AA mediated hypertension in these rats [48][31]. Therefore, AT1-AA serves as a possible therapeutic target for treating preeclampsia. Moreover, previous studies have shown that maternal AT1-AA persisted up to 27 months after pregnancy in 17.2% of women with preeclampsia compared to 2.9% in women with normotensive pregnancy [49][32]. Recently, a follow up study on circulating AT1-AA levels at five to eight years postpartum was published which showed that AT1-AA was persistently found in women with a history of preeclampsia, which might relate to their future CVD risk [50][33].

3.4. Angiogenic/Antiangiogenic Factors

Angiogenic factors are most highly expressed in early pregnancy and are responsible for placental angiogenesis and increasing placental mass that follows fetal growth [51][34]. Previous studies have revealed that RUPP leads to altered concentrations of pro- and anti-angiogenic factors in women with preeclampsia, which leads to endothelial dysfunction and suggests that they are responsible for the pathology of maternal clinical manifestations of preeclampsia [52][35].

3.4.1. Vascular Endothelial Growth Factors (VEGF)

The VEGF family includes [VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF)], and their receptors [VEGFR-1/fms-like tyrosine kinase-1 (Flt-1), VEGFR-2/kinase insert domain receptor (KDR), VEGFR-3/fms-like tyrosine kinase receptor-4(Flt-4)]. Vascular endothelial growth factor (VEGF) is highly expressed in decidual cells and invading cytotrophoblasts in normal pregnancy, which leads to endothelial cell proliferation for newly developing capillaries in uteroplacental circulation [53][36]. Moreover, VEGF-A regulates trophoblast functions such as proliferation, differentiation, and invasion, mainly through the Flt-1 and KDR receptors [54][37]. In preeclampsia, the circulating level of VEGF is decreased and this has been confirmed in studies with RUPP-induced rats in which the VEGF level is also reduced [55,56][38][39].

3.4.2. Placental Growth Factor (PlGF)

Placental growth factor (PlGF), a member of the VEGF family, is another proangiogenic factor that binds to Flt-1 which augments the angiogenic effect of VEGF. PlGF exerts not only direct effects on endothelial cells, but also indirect effects on nonvascular cells with pro-angiogenic activity by altering the functioning of immune cells; it recruits monocytes and activates macrophages which can release angiogenic factors, and encourages proliferation of mesenchymal fibroblasts and attracts myeloid progenitors to develop sprouts and collateral vessels [57][40]. Moreover, PlGF promotes vasodilation of uteroplacental circulation [36][19]. However, the circulating level of PlGF is decreased in preeclampsia compared to normal pregnancy, which leads to increased vascular resistance in preeclampsia [58][41]. Therefore, the National Institute for Health and Care Excellence guideline has recommended that obstetricians to utilize maternal serum PlGF levels to rule out preeclampsia in pregnant women with chronic hypertension or who are at a high risk of developing preeclampsia [59][42].

3.4.3. Soluble FMS-Like Tyrosine Kinase I (sFlt-1)

As a VEGF receptor, Flt-1 is highly expressed in the invading extravillous trophoblasts in the first trimester, which implies that VEGF-Flt-1 interactions lead to early trophoblast invasion [60][43]. As gestational age develops, VEGF-Flt-1 interaction also guides trophoblast differentiation and migration [61][44]. Soluble FMS-like tyrosine kinase I (sFlt-1) is a truncated protein resulting from splicing of Flt-1 which lacks the cytoplasmic and transmembrane domain but keeps the ligand-binding domain [62][45]. Therefore, sFlt-1 antagonizes and inhibits VEGF and PlGF by binding to them and blocking their interaction with Flt-1 for proangiogenic function. In preeclampsia, placental ischemia resulting from RUPP may stimulate upregulation of sFlt-1 by binding of hypoxia inducible factor (HIF) to the promotor of Flt-1 gene [55][38]. The elevated maternal serum level of sFlt-1 in preeclampsia has been found to be associated with severe endothelial dysfunction and inhibition of VEGF and PlGF by sFlt-1 serves a major pathogenic role in hypertension and proteinuria [5][1]. VEGF is responsible for decreasing vascular tone and blood pressure by inducing nitric oxide and prostacyclins that have a vasodilatory effect in endothelial cells, which is blocked by sFlt-1. In addition, several molecular mechanisms of sFlt-1 found to be responsible for renal dysfunction are related to glomerular capillary endotheliosis, dysregulation of the glomerular filtration apparatus, and podocyte loss [63][46]. Therefore, excess of sFlt-1 results in the characteristic antiangiogenic state of preeclampsia which manifests as the clinical syndrome of endothelial dysfunction. In fact, maternal serum level of sFlt-1 to PlGF ratio (sFlt-1/PlGF ratio) can be used as a reliable biomarker for predicting development and severity of preeclampsia [64][47]. Moreover, a recent systematic review and meta-analysis on the performance of the sFlt-1/PlGF ratio in predicting adverse outcomes in women diagnosed or suspected of preeclampsia showed that the sFlt-1/PlGF ratio performs better in predicting women with early onset preeclampsia in comparison to those with late onset [65][48]; this relates to our previous topic in chapter 4 which described that defective uteroplacental vascular remodeling is mostly seen in the early onset type of preeclampsia.

3.4.4. Soluble Endoglin (sEng)

Soluble endoglin (sEng), a coreceptor for transforming growth factor-β1 (TGF-β1), is another antiangiogenic factor released by the placenta that acts in synergy with sFlt-1. Endoglin (Eng) is an angiogenic receptor expressed mainly on the surface of placental syncytiotrophoblast and endothelial cells which serves as a co-receptor of angiogenic TGF-β signaling [66][49]. TGF-β is known to contribute to angiogenesis and appropriate vascular relaxation by increasing VEGF [67,68][50][51]. However, in preeclampsia sEng is released in excessive quantity and binds to free TGF-β1 which inhibits the pro-angiogenic TGF-β1 signaling in the vasculature. The circulating level of sEng is elevated in patients with preeclampsia two-to-three months prior to the onset of clinical symptoms and its serum levels seem to be correlated with the severity of the disease [69][52].

3.5. Activin A

Activin A is a dimeric glycoprotein belonging to the TGF-β family produced by the placenta and fetal membranes [70][53]. In preeclampsia, the serum level of activin A is elevated (up to 10-fold) compared to normal pregnancy and it is found to be resulting from increased placental production triggered by oxidative stress [71,72][54][55]. In fact, circulating levels of activin A have shown to rise months prior to the onset of the clinical manifestation of preeclampsia, which is earlier than the elevation of sFlt-1 or sEng [73][56]. Recent studies have shown that elevated activin A in preeclampsia may be responsible for the endothelial dysfunction, which was shown as hypertension, proteiunuria, fetal growth restriction, and preterm littering in activin administered mice [74][57]. An in vitro study using human umbilical vein endothelial cells (HUVECs) has suggested that activin A up-regulates transcription of endothelial vasoconstrictors such as ET-1 [75][58]. Moreover, an elevated activin A level had been reported to be strongly correlated with myocardial dysfunction at 1 year after preeclamptic pregnancy, and a recent follow up study confirmed that the activin A level still remained elevated with impaired cardiac function 10 years after preeclamptic pregnancy, implying its potential use as a tool for monitoring women at risk for postpartum CVD [76,77][59][60].

3.6. Hypoxia Inducible Factor

Hypoxia inducible factor (HIF) is a heterodimer consisting of HIF1-α and HIF2-α subunits, which are regulated by oxygen, and a constitutively expressed HIF1-β subunit. In a hypoxic environment, HIF-1 regulates transcription of various genes, including VEGF, TGF-β3, and NOS, by binding at their promotor and enhancer regions [36][19]. HIF expression is shown to be higher in normal pregnancy, probably due to high estrogen and progesterone levels; however, HIF-1α and HIF-2α is overexpressed further in preeclampsia in response to RUPP [78,79][61][62]. Moreover, HIF-1α upregulates anti-angiogenic factors such as sFlt-1, sEng, and ET-1 expressions and AngII and AngII-converting enzyme (ACE) expressions in the lungs and kidney which add on to the abnormal placentation and development of preeclampsia [80][63]. An animal study with RUPP rats showed that inhibition of HIF-1α using siRNA reversed the high blood pressure, renal damage, proteinuria, and elevated serum sFlt-1 level [81][64]. Therefore, the efficacy of using maternal serum level of HIF-1α as a predictive marker for preeclampsia has been questioned. A recent prospective study showed that high serum HIF-1α level (above 1.45 MoM) in the first trimester of pregnancy (11–13+6 weeks of gestation) was related to development of preeclampsia, which requires further confirmation with large-scaled studies [82][65].

3.7. MicroRNAs

MicroRNAs(miRNAs) are small (<25 nucleotides), single-stranded, non-coding RNAs that regulate gene expression by inhibiting translation. These molecules bind to the untranslated lesion of a target gene and silence their expression [83][66]. During pregnancy, miRNAs are profusely expressed in the placenta, mainly from villous trophoblasts, and play pivotal role in several processes including trophoblast proliferation, immune tolerance, and angiogenesis [84][67].
Specifically, miR-210 has been reported to be overexpressed in placentas of preeclampsia [85][68]. Studies have shown that miR-210 is strongly linked with hypoxia related to RUPP which leads to inadequate trophoblast invasion and failure of spiral artery remodeling in preeclampsia [86][69]. miR-210 is upregulated by HIF which overexpresses it in response uteroplacental hypoxia in order to regulate genes involved in various pathways including angiogenesis, inflammation, and cell proliferation [87][70]. Another miRNA involved in preeclampsia is miR-155, which has been shown to inhibit cysteine-rich protein 61 (CYR61), an essential angiogenic factor in pregnancy [88,89][71][72]. A crucial function of CYR61 is related to inducing the expression of VEGF, which is a major pro-angiogenic factor as previously mentioned [87][70]. Previous studies have shown that CYR61 gene expression is downregulated in preeclamptic placentas compared to those of normal pregnancy, and suggested that increased miR-155 causes inhibition of the CYR61-VEGF pathways, which leads to reduced placental angiogenesis [90][73].
Additionally, miR-125b is known to be an anti-angiogenic factor which decreases VEGF expression when it is overexpressed [91][74]. A recent case-control study showed that the maternal plasma level of miR-125b at 12 weeks of gestation is significantly elevated compared to those in normal pregnancy. Moreover, the same study revealed that miR-125b targets trophoblast cell surface antigen-2 (Trop-2) protein in placental tissue, suggesting miR-125b might be involved in development of preeclampsia via modulating Trop-2 expression in the syncitiotrophoblast [92][75].
The role of miR-21 in preeclampsia has been also newly studied, since it regulates the forkhead box M1 protein (FOXM1), which is expressed in cytotrophoblasts for proliferation and differentiation, responsible for the early placental development [93][76]. In fact, a study showed that miR-21 is elevated with reduced FOXM1 expression in patients with preeclampsia compared to those in normotensive pregnant women, implying that miR-21 may impede the early placental invasion leading to preeclampsia [94][77]. These results demonstrate that various miRNAs are involved in the pathway of preeclampsia which implies their potential to become possible future therapeutic targets for treatment of preeclampsia.

References

  1. Hong, K.; Park, H.J.; Cha, D.H. Clinical implications of placenta-derived angiogenic/anti-angiogenic biomarkers in pre-eclampsia. Biomark. Med. 2021, 15, 523–536.
  2. Lyall, F. The human placental bed revisited. Placenta 2002, 23, 555–562.
  3. Brosens, I.A.; Robertson, W.B.; Dixon, H.G. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet. Gynecol. Annu. 1972, 1, 177–191.
  4. Pijnenborg, R.; Vercruysse, L.; Hanssens, M. The uterine spiral arteries in human pregnancy: Facts and controversies. Placenta 2006, 27, 939–958.
  5. Sato, Y. Endovascular trophoblast and spiral artery remodeling. Mol. Cell. Endocrinol. 2020, 503, 110699.
  6. Chaiworapongsa, T.; Chaemsaithong, P.; Yeo, L.; Romero, R. Pre-eclampsia part 1: Current understanding of its pathophysiology. Nat. Rev. Nephrol. 2014, 10, 466–480.
  7. Sheppard, B.L.; Bonnar, J. An ultrastructural study of utero-placental spiral arteries in hypertensive and normotensive pregnancy and fetal growth retardation. Br. J. Obstet. Gynaecol. 1981, 88, 695–705.
  8. Brosens, I.; Pijnenborg, R.; Vercruysse, L.; Romero, R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 2011, 204, 193–201.
  9. Kim, Y.M.; Chaiworapongsa, T.; Gomez, R.; Bujold, E.; Yoon, B.H.; Rotmensch, S.; Thaler, H.T.; Romero, R. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am. J. Obstet. Gynecol. 2002, 187, 1137–1142.
  10. Romero, R.; Kusanovic, J.P.; Chaiworapongsa, T.; Hassan, S.S. Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae. Best Pract. Res. Clin. Obstet. Gynaecol. 2011, 25, 313–327.
  11. Moreno-Eutimio, M.A.; Tovar-Rodríguez, J.M.; Vargas-Avila, K.; Nieto-Velázquez, N.G.; Frías-De-León, M.G.; Sierra-Martinez, M.; Acosta-Altamirano, G. Increased serum levels of inflammatory mediators and low frequency of regulatory T cells in the peripheral blood of preeclamptic Mexican women. Biomed. Res. Int. 2014, 2014, 413249.
  12. Sánchez-Aranguren, L.C.; Prada, C.E.; Riaño-Medina, C.E.; Lopez, M. Endothelial dysfunction and preeclampsia: Role of oxidative stress. Front. Physiol. 2014, 5, 372.
  13. Lockwood, C.J.; Yen, C.F.; Basar, M.; Kayisli, U.A.; Martel, M.; Buhimschi, I.; Buhimschi, C.; Huang, S.J.; Krikun, G.; Schatz, F. Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells. Am. J. Pathol. 2008, 172, 1571–1579.
  14. Wallace, K.; Richards, S.; Dhillon, P.; Weimer, A.; Edholm, E.S.; Bengten, E.; Wilson, M.; Martin, J.N., Jr.; LaMarca, B. CD4+ T-helper cells stimulated in response to placental ischemia mediate hypertension during pregnancy. Hypertension 2011, 57, 949–955.
  15. Lamarca, B.; Brewer, J.; Wallace, K. IL-6-induced pathophysiology during pre-eclampsia: Potential therapeutic role for magnesium sulfate? Int. J. Interferon. Cytokine Mediat. Res. 2011, 2011, 59–64.
  16. Peixoto, A.B.; Araujo Júnior, E.; Ribeiro, J.U.; Rodrigues, D.B.; Castro, E.C.; Caldas, T.M.; Rodrigues Júnior, V. Evaluation of inflammatory mediators in the deciduas of pregnant women with pre-eclampsia/eclampsia. J. Matern. Fetal Neonatal. Med. 2016, 29, 75–79.
  17. Cornelius, D.C.; Amaral, L.M.; Harmon, A.; Wallace, K.; Thomas, A.J.; Campbell, N.; Scott, J.; Herse, F.; Haase, N.; Moseley, J.; et al. An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2015, 309, R884–R891.
  18. Nath, M.C.; Cubro, H.; McCormick, D.J.; Milic, N.M.; Garovic, V.D. Preeclamptic Women Have Decreased Circulating IL-10 (Interleukin-10) Values at the Time of Preeclampsia Diagnosis: Systematic Review and Meta-Analysis. Hypertension 2020, 76, 1817–1827.
  19. Shah, D.A.; Khalil, R.A. Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia. Biochem. Pharmacol. 2015, 95, 211–226.
  20. Reslan, O.M.; Khalil, R.A. Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia. Cardiovasc. Hematol. Agents Med. Chem. 2010, 8, 204–226.
  21. Bainbridge, S.A.; Belkacemi, L.; Dickinson, M.; Graham, C.H.; Smith, G.N. Carbon monoxide inhibits hypoxia/reoxygenation-induced apoptosis and secondary necrosis in syncytiotrophoblast. Am. J. Pathol. 2006, 169, 774–783.
  22. Chambers, J.C.; Fusi, L.; Malik, I.S.; Haskard, D.O.; De Swiet, M.; Kooner, J.S. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001, 285, 1607–1612.
  23. Sutton, E.F.; Gemmel, M.; Powers, R.W. Nitric oxide signaling in pregnancy and preeclampsia. Nitric Oxide 2020, 95, 55–62.
  24. Guerby, P.; Tasta, O.; Swiader, A.; Pont, F.; Bujold, E.; Parant, O.; Vayssiere, C.; Salvayre, R.; Negre-Salvayre, A. Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia. Redox Biol. 2021, 40, 101861.
  25. Chassagne, C.; Eddahibi, S.; Adamy, C.; Rideau, D.; Marotte, F.; Dubois-Randé, J.L.; Adnot, S.; Samuel, J.L.; Teiger, E. Modulation of angiotensin II receptor expression during development and regression of hypoxic pulmonary hypertension. Am. J. Respir. Cell. Mol. Biol. 2000, 22, 323–332.
  26. Anton, L.; Merrill, D.C.; Neves, L.A.; Diz, D.I.; Corthorn, J.; Valdes, G.; Stovall, K.; Gallagher, P.E.; Moorefield, C.; Gruver, C.; et al. The uterine placental bed Renin-Angiotensin system in normal and preeclamptic pregnancy. Endocrinology 2009, 150, 4316–4325.
  27. Quitterer, U.; Fu, X.; Pohl, A.; Bayoumy, K.M.; Langer, A.; AbdAlla, S. Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers. Cell 2019, 176, 318–333.e19.
  28. Zanaty, M.; Seara, F.A.C.; Nakagawa, P.; Deng, G.; Mathieu, N.M.; Balapattabi, K.; Karnik, S.S.; Grobe, J.L.; Sigmund, C.D. β-Arrestin-Biased Agonist Targeting the Brain AT(1)R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate-Salt Hypertension. Hypertension 2021, 77, 420–431.
  29. Siddiqui, A.H.; Irani, R.A.; Zhang, W.; Wang, W.; Blackwell, S.C.; Kellems, R.E.; Xia, Y. Angiotensin receptor agonistic autoantibody-mediated soluble fms-like tyrosine kinase-1 induction contributes to impaired adrenal vasculature and decreased aldosterone production in preeclampsia. Hypertension 2013, 61, 472–479.
  30. George, E.M.; Granger, J.P. Endothelin: Key mediator of hypertension in preeclampsia. Am. J. Hypertens. 2011, 24, 964–969.
  31. Novotny, S.R.; Wallace, K.; Heath, J.; Moseley, J.; Dhillon, P.; Weimer, A.; Wallukat, G.; Herse, F.; Wenzel, K.; Martin, J.N., Jr.; et al. Activating autoantibodies to the angiotensin II type I receptor play an important role in mediating hypertension in response to adoptive transfer of CD4+ T lymphocytes from placental ischemic rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 302, R1197–R1201.
  32. Hubel, C.A.; Wallukat, G.; Wolf, M.; Herse, F.; Rajakumar, A.; Roberts, J.M.; Markovic, N.; Thadhani, R.; Luft, F.C.; Dechend, R. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension 2007, 49, 612–617.
  33. Rieber-Mohn, A.B.; Sugulle, M.; Wallukat, G.; Alnæs-Katjavivi, P.; Leite Størvold, G.; Bolstad, N.; Redman, C.W.; Dechend, R.; Staff, A.C. Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum. J. Reprod. Immunol. 2018, 128, 23–29.
  34. Bdolah, Y.; Sukhatme, V.P.; Karumanchi, S.A. Angiogenic imbalance in the pathophysiology of preeclampsia: Newer insights. Semin. Nephrol. 2004, 24, 548–556.
  35. Boeldt, D.S.; Bird, I.M. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J. Endocrinol. 2017, 232, R27–R44.
  36. Charnock-Jones, D.S.; Sharkey, A.M.; Boocock, C.A.; Ahmed, A.; Plevin, R.; Ferrara, N.; Smith, S.K. Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol. Reprod. 1994, 51, 524–530.
  37. Athanassiades, A.; Hamilton, G.S.; Lala, P.K. Vascular endothelial growth factor stimulates proliferation but not migration or invasiveness in human extravillous trophoblast. Biol. Reprod. 1998, 59, 643–654.
  38. Maynard, S.E.; Min, J.Y.; Merchan, J.; Lim, K.H.; Li, J.; Mondal, S.; Libermann, T.A.; Morgan, J.P.; Sellke, F.W.; Stillman, I.E.; et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Investig. 2003, 111, 649–658.
  39. Gilbert, J.S.; Babcock, S.A.; Granger, J.P. Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension 2007, 50, 1142–1147.
  40. Albonici, L.; Giganti, M.G.; Modesti, A.; Manzari, V.; Bei, R. Multifaceted Role of the Placental Growth Factor (PlGF) in the Antitumor Immune Response and Cancer Progression. Int. J. Mol. Sci. 2019, 20, 2970.
  41. March, M.I.; Geahchan, C.; Wenger, J.; Raghuraman, N.; Berg, A.; Haddow, H.; McKeon, B.A.; Narcisse, R.; David, J.L.; Scott, J.; et al. Circulating Angiogenic Factors and the Risk of Adverse Outcomes among Haitian Women with Preeclampsia. PLoS ONE 2015, 10, e0126815.
  42. National Institute for Health and Care Excellence: Clinical Guidelines. Hypertension in Pregnancy: Diagnosis and Management; National Institute for Health and Care Excellence: London, UK, 2019.
  43. Wulff, C.; Wilson, H.; Dickson, S.E.; Wiegand, S.J.; Fraser, H.M. Hemochorial placentation in the primate: Expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy. Biol. Reprod. 2002, 66, 802–812.
  44. Geva, E.; Ginzinger, D.G.; Zaloudek, C.J.; Moore, D.H.; Byrne, A.; Jaffe, R.B. Human placental vascular development: Vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J. Clin. Endocrinol. Metab. 2002, 87, 4213–4224.
  45. Kendall, R.L.; Thomas, K.A. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. USA 1993, 90, 10705–10709.
  46. Sircar, M.; Thadhani, R.; Karumanchi, S.A. Pathogenesis of preeclampsia. Curr. Opin. Nephrol. Hypertens. 2015, 24, 131–138.
  47. Verlohren, S.; Herraiz, I.; Lapaire, O.; Schlembach, D.; Zeisler, H.; Calda, P.; Sabria, J.; Markfeld-Erol, F.; Galindo, A.; Schoofs, K.; et al. New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension 2014, 63, 346–352.
  48. Lim, S.; Li, W.; Kemper, J.; Nguyen, A.; Mol, B.W.; Reddy, M. Biomarkers and the Prediction of Adverse Outcomes in Preeclampsia: A Systematic Review and Meta-analysis. Obstet. Gynecol. 2021, 137, 72–81.
  49. Cheifetz, S.; Bellón, T.; Calés, C.; Vera, S.; Bernabeu, C.; Massagué, J.; Letarte, M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J. Biol. Chem. 1992, 267, 19027–19030.
  50. Goumans, M.J.; Valdimarsdottir, G.; Itoh, S.; Rosendahl, A.; Sideras, P.; ten Dijke, P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002, 21, 1743–1753.
  51. Park, S.; Sorenson, C.M.; Sheibani, N. PECAM-1 isoforms, eNOS and endoglin axis in regulation of angiogenesis. Clin. Sci. 2015, 129, 217–234.
  52. Venkatesha, S.; Toporsian, M.; Lam, C.; Hanai, J.; Mammoto, T.; Kim, Y.M.; Bdolah, Y.; Lim, K.H.; Yuan, H.T.; Libermann, T.A.; et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 2006, 12, 642–649.
  53. Rabinovici, J.; Goldsmith, P.C.; Librach, C.L.; Jaffe, R.B. Localization and regulation of the activin-A dimer in human placental cells. J. Clin. Endocrinol. Metab. 1992, 75, 571–576.
  54. Muttukrishna, S.; Knight, P.G.; Groome, N.P.; Redman, C.W.; Ledger, W.L. Activin A and inhibin A as possible endocrine markers for pre-eclampsia. Lancet 1997, 349, 1285–1288.
  55. Manuelpillai, U.; Schneider-Kolsky, M.; Dole, A.; Wallace, E.M. Activin A and activin receptors in gestational tissue from preeclamptic pregnancies. J. Endocrinol. 2001, 171, 57–64.
  56. Muttukrishna, S.; North, R.A.; Morris, J.; Schellenberg, J.C.; Taylor, R.S.; Asselin, J.; Ledger, W.; Groome, N.; Redman, C.W. Serum inhibin A and activin A are elevated prior to the onset of pre-eclampsia. Hum. Reprod. 2000, 15, 1640–1645.
  57. Lim, R.; Acharya, R.; Delpachitra, P.; Hobson, S.; Sobey, C.G.; Drummond, G.R.; Wallace, E.M. Activin and NADPH-oxidase in preeclampsia: Insights from in vitro and murine studies. Am. J. Obstet. Gynecol. 2015, 212, 86.e1–86.e12.
  58. Hobson, S.R.; Lim, R.; Mockler, J.C.; Gurusinghe, S.; Wallace, E.M. Role of Activin A in the Pathogenesis of Endothelial Cell Dysfunction in Preeclampsia. Methods Mol. Biol. 2018, 1710, 39–52.
  59. Shahul, S.; Ramadan, H.; Nizamuddin, J.; Mueller, A.; Patel, V.; Dreixler, J.; Tung, A.; Lang, R.M.; Weinert, L.; Nasim, R.; et al. Activin A and Late Postpartum Cardiac Dysfunction Among Women With Hypertensive Disorders of Pregnancy. Hypertension 2018, 72, 188–193.
  60. de Martelly, V.A.; Dreixler, J.; Tung, A.; Mueller, A.; Heimberger, S.; Fazal, A.A.; Naseem, H.; Lang, R.; Kruse, E.; Yamat, M.; et al. Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia. J. Am. Heart Assoc. 2021, 10, e018526.
  61. Daikoku, T.; Matsumoto, H.; Gupta, R.A.; Das, S.K.; Gassmann, M.; DuBois, R.N.; Dey, S.K. Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is regulated in a cell-specific and ovarian steroid hormone-dependent manner. Evidence for differential function of HIFs during early pregnancy. J. Biol. Chem. 2003, 278, 7683–7691.
  62. Akhilesh, M.; Mahalingam, V.; Nalliah, S.; Ali, R.M.; Ganesalingam, M.; Haleagrahara, N. Hypoxia-inducible factor-1α as a predictive marker in pre-eclampsia. Biomed. Rep. 2013, 1, 257–258.
  63. Tal, R. The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis. Biol. Reprod. 2012, 87, 134.
  64. Iriyama, T.; Wang, W.; Parchim, N.F.; Song, A.; Blackwell, S.C.; Sibai, B.M.; Kellems, R.E.; Xia, Y. Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia. Hypertension 2015, 65, 1307–1315.
  65. Tianthong, W.; Phupong, V. Serum hypoxia-inducible factor-1α and uterine artery Doppler ultrasound during the first trimester for prediction of preeclampsia. Sci. Rep. 2021, 11, 6674.
  66. Krek, A.; Grün, D.; Poy, M.N.; Wolf, R.; Rosenberg, L.; Epstein, E.J.; MacMenamin, P.; da Piedade, I.; Gunsalus, K.C.; Stoffel, M.; et al. Combinatorial microRNA target predictions. Nat. Genet. 2005, 37, 495–500.
  67. Li, H.; Ge, Q.; Guo, L.; Lu, Z. Maternal plasma miRNAs expression in preeclamptic pregnancies. Biomed. Res. Int. 2013, 2013, 970265.
  68. Pineles, B.L.; Romero, R.; Montenegro, D.; Tarca, A.L.; Han, Y.M.; Kim, Y.M.; Draghici, S.; Espinoza, J.; Kusanovic, J.P.; Mittal, P.; et al. Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am J. Obstet. Gynecol. 2007, 196, 261.e1–261.e6.
  69. Zhang, Y.; Fei, M.; Xue, G.; Zhou, Q.; Jia, Y.; Li, L.; Xin, H.; Sun, S. Elevated levels of hypoxia-inducible microRNA-210 in pre-eclampsia: New insights into molecular mechanisms for the disease. J. Cell. Mol. Med. 2012, 16, 249–259.
  70. Bounds, K.R.; Chiasson, V.L.; Pan, L.J.; Gupta, S.; Chatterjee, P. MicroRNAs: New Players in the Pathobiology of Preeclampsia. Front. Cardiovasc. Med. 2017, 4, 60.
  71. Lázár, L.; Rigó, J. PP088. The role of microRNA in pathogenesis of preeclampsia-miRNA network analysis. Pregnancy Hypertens. 2013, 3, 99.
  72. Zhang, Y.; Diao, Z.; Su, L.; Sun, H.; Li, R.; Cui, H.; Hu, Y. MicroRNA-155 contributes to preeclampsia by down-regulating CYR61. Am. J. Obstet. Gynecol. 2010, 202, 466.e1–466.e7.
  73. Gellhaus, A.; Schmidt, M.; Dunk, C.; Lye, S.J.; Kimmig, R.; Winterhager, E. Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia. Mol. Hum. Reprod. 2006, 12, 389–399.
  74. He, J.; Jing, Y.; Li, W.; Qian, X.; Xu, Q.; Li, F.S.; Liu, L.Z.; Jiang, B.H.; Jiang, Y. Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis. PLoS ONE 2013, 8, e56647.
  75. Licini, C.; Avellini, C.; Picchiassi, E.; Mensà, E.; Fantone, S.; Ramini, D.; Tersigni, C.; Tossetta, G.; Castellucci, C.; Tarquini, F.; et al. Pre-eclampsia predictive ability of maternal miR-125b: A clinical and experimental study. Transl. Res. 2021, 228, 13–27.
  76. Gao, F.; Bian, F.; Ma, X.; Kalinichenko, V.V.; Das, S.K. Control of regional decidualization in implantation: Role of FoxM1 downstream of Hoxa10 and cyclin D3. Sci. Rep. 2015, 5, 13863.
  77. Zhou, F.; Sun, Y.; Gao, Q.; Wang, H. microRNA-21 regulates the proliferation of placental cells via FOXM1 in preeclampsia. Exp. Ther. Med. 2020, 20, 1871–1878.
More