Is the imbalance between pro-angiogenic and anti-angiogenic factors associated with preeclampsia?

Jardim, Letícia Lemos; Rios, Danyelle Romana Alves; Perucci, Luíza Oliveira; Sousa, Lirlândia P.; Gomes, Karina Braga; Dusse, Luci Maria S.

doi:10.1016/j.cca.2015.05.004

Cited by 64 publications

(64 citation statements)

References 49 publications

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“…For instance, sFlt-1 e15a, a splice variant of sFlt-1 that is abundantly expressed by syncytiotrophoblasts and released by the placenta, has been shown to bind VEGF and decrease endothelial cell migration, invasion, and tube formation, and its serum levels show 10-fold increase in preeclamptic vs normal pregnant women [87]. Also, soluble endoglin (sEng) is an anti-angiogenic factor that binds TGF-β1 and inhibits its signaling effects [25]. The levels of sEng are higher in preeclampsia and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome compared with normal pregnant women [21, 88], and the serum and placenta levels of sEng are increased while serum TGF-β levels are decreased in RUPP rats [61].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…VEGF gene expresses a family of proteins including VEGF-A, -B, -C, -D and PlGF [25]. VEGF-A, VEGF-B and PlGF bind to tyrosine kinase receptor Flt-1 (VEGFR-1) and VEGF-A binds to VEGFR-2 (Flk-1 or KDR) to promote placental vascularization [25]. Measurements of circulating levels of VEGF in preeclampsia have not been consistent, with studies showing decreased [26], unchanged [27, 28] or even increased levels [29–31].…”

Section: Introductionmentioning

confidence: 99%

“…Circulating levels of sFlt-1 are 10-fold higher in pregnant than non-pregnant women, remain almost stable during the first and second trimester, then increase after the 36 th week of gestation and throughout the third trimester [20]. The circulating sFlt-1 levels and sFlt-1/PlGF ratio are much higher in preeclamptic than normal pregnant women from the second trimester onwards [25, 29, 33, 35, 36]. These observations suggest that angiogenic imbalance could be a mechanism linking RUPP to HTN-Preg.…”

Section: Introductionmentioning

confidence: 99%

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Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Dias‐Junior

Chen

Cui

et al. 2017

Biochemical Pharmacology

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Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Dias‐Junior

Chen

Cui

et al. 2017

Biochemical Pharmacology

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“…PE could develop at early gestational age <34 weeks or late gestational age ≥34 weeks (Jardim et al, 2015). Early PE is generally linked to compromised trophoblast invasion, placental hypoxia and release of bioactive factors that could target the endothelium, while late PE has been linked to preexisting maternal conditions that could affect endothelial integrity (Brandao et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Possomato-Vieira

Khalil

2016

Advances in Pharmacology

191

117

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Preeclampsia is a pregnancy-related disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia.

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Placental‐Specific Overexpression of sFlt‐1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model

Kühnel

Kleff

Stojanovska

et al. 2017

J of Cellular Biochemistry

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Since it is known that placental overexpression of the human anti-angiogenic molecule sFlt-1, the main candidate in the progression of preeclampsia, lead to intrauterine growth restriction (IUGR) in mice by lentiviral transduction of mouse blastocysts, we hypothesize that sFlt-1 influence placental morphology and physiology resulting in fetal IUGR. We therefore examined the effect of sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Interestingly, placental overexpression of sFlt-1 leads to IUGR in the fetus and results in lower placental weights. Moreover, we observed altered trophoblast differentiation with reduced expression of IGF2, resulting in a smaller placenta, a smaller labyrinth, and the loss of glycogen cells in the junctional zone. Changes in IGF2 are accompanied by small changes in its DNA methylation, whereas overall DNA methylation is unaffected. In addition, the expression of placental nutrient transporters, such as the glucose diffusion channel Cx26, is decreased. In contrast, the expression of the fatty acid transporter CD36 and the cholesterol transporter ABCA1 is significantly increased. In conclusion, placental sFlt-1 overexpression resulted in a reduction in the differentiation of the spongiotrophoblast into glycogen cells. These findings of a reduced exchange area of the labyrinth and glycogen stores, as well as decreased expression of glucose transporter, could contribute to the intrauterine growth restriction phenotype. All of these factors change the intrauterine availability of nutrients. Thus, we speculate that the alterations triggered by increased anti-angiogenesis strongly affect fetal outcome and programming. J. Cell. Biochem. 118: 1316-1329, 2017. © 2016 Wiley Periodicals, Inc.

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Is the imbalance between pro-angiogenic and anti-angiogenic factors associated with preeclampsia?

Cited by 64 publications

References 49 publications

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Placental‐Specific Overexpression of sFlt‐1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model

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