sFlt-1 In Pregnancies Research Articles

Association of vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 polymorphisms with their circulating protein levels in preeclampsia

Introduction: Normal development of placental vascular tree requiring angiogenesis and vasculogenesis is structurally and functionally indispensable for both adequate placental growth and delivery of nutrients from mother to the fetus. Impaired placental angiogenesis has been implicated in the pathophysiology of pregnancy complications which have immediate and long-lasting effects on the mother and her child, such as preeclampsia (PE) and fetal growth restriction. The mechanisms underlying the deregulation of placental angiogenesis in PE include a misbalance between the secretion and activity of pro-angiogenic (vascular endothelial growth factor [VEGF]) and anti-angiogenic (soluble fms-like tyrosine kinase-1 [sFlt-1]) factors. Considering the important roles of VEGF and sflt1 in pregnancy, functional polymorphisms in these genes may be potentially important as genetic markers for susceptibility to PE. Thus, the aim of the study was to screen for the presence of VEGF and sFlt-1 gene polymorphisms and to measure their levels in PE patients and controls of Indian origin. Material and Methods: Fifty each of clinically diagnosed patients and gestational and maternal age-matched normotensive, nonproteinuric controls were recruited after taking informed consent. DNA isolated from blood samples was processed for polymerase chain reaction amplification followed by restriction fragment length polymorphism to screen for the presence of VEGF + 936C/T, sFlt-1 (+4244G/A, −4771G/T, −523C/G) polymorphisms. Serum levels of VEGF-A and sFlt-1 were measured by Sandwich enzyme-linked immunosorbent assay (ELISA). Results: Decreased frequency of wild type genotype with respect to VEGF + 936C/T and sFlt-1 (+4244G/A, −4771G/T, and −523C/G) polymorphisms was seen in patients. ELISA results showed lower VEGF-A (198.43 ± 14.63 pg/ml vs. 235.08 ± 16.72 pg/ml [mean ± standard error of mean]) and higher sFlt-1 levels (2932.81 [1802.33–5760.46] pg/ml vs. 1114.94 [655.03–2694.35] Median [Range]; P

In vivo experiments reveal the good, the bad and the ugly faces of sFlt-1 in pregnancy.

ObjectiveSoluble fms-like tyrosine kinase (sFlt)-1-e15a, a primate-specific sFlt-1-isoform most abundant in the human placenta in preeclampsia, can induce preeclampsia in mice. This study compared the effects of full-length human (h)sFlt-1-e15a with those of truncated mouse (m)sFlt-1(1-3) used in previous preeclampsia studies on pregnancy outcome and clinical symptoms in preeclampsia.MethodsMice were injected with adenoviruses or fiber-mutant adenoviruses overexpressing hsFlt-1-e15a, msFlt-1(1-3) or control GFP under the CMV or CYP19A1 promoters on gestational day 8 (GD8) and GD11. Placentas and pups were delivered by cesarean section, and dams were monitored postpartum. Blood pressure was telemetrically recorded. Urine samples were collected with cystocentesis and examined for albumin/creatinine ratios. Tissue specimens were evaluated for transgene as well as endogenous mFlt-1 and msFlt-1-i13 expression. H&E-, Jones- and PAS-stained kidney sections were histopathologically examined. Placental GFP expression and aortic ring assays were investigated with confocal microscopy.ResultsMean arterial blood pressure (MAP) was elevated before delivery in hsFlt-1-e15a-treated mice compared to controls (GD18: ΔMAP = 7.8 mmHg, p = 0.009), while ΔMAP was 12.8 mmHg (GD18, p = 0.005) in msFlt-1(1-3)-treated mice. Urine albumin/creatinine ratio was higher in hsFlt-1-e15a-treated mice than in controls (GD18, p = 0.04; PPD8, p = 0.03), and msFlt-1(1-3)-treated mice had marked proteinuria postpartum (PPD8, p = 4×10−5). Focal glomerular changes were detected in hsFlt-1-e15a and msFlt-1(1-3)-treated mice. Aortic ring microvessel outgrowth was decreased in hsFlt-1-e15a (p = 0.007) and msFlt-1(1-3)-treated (p = 0.02) mice. Full-length msFlt-1-i13 expression was unique for the placenta. In hsFlt-1-e15a-treated mice, the number of pups (p = 0.046), total weight of living pups (p = 0.04) and maternal weights (p = 0.04) were higher than in controls. These differences were not observed in truncated msFlt-1(1-3)-treated mice.ConclusionsTruncated msFlt-1(1-3) simulated the preeclampsia-promoting effects of full-length hsFlt-1. MsFlt-1(1-3) had strong effect on maternal endothelium but not on placentas and embryos. In contrast, hsFlt-1-e15a induced preeclampsia-like symptoms; however, it also increased litter size. In accord with the predominant placental expression of hsFlt-1-e15a and msFlt-1-i13, full-length sFlt-1 may have a role in the regulation of embryonic development. These observations point to the difference in the biological effects of full-length and truncated sFlt-1 and the changes in the effect of full-length sFlt-1 during pregnancy, and may have important implications in the management of preeclampsia.

Analysis of the sFlt-1 in pregnancies complicated by preeclampsia with and without IUGR

Analysis of the sFlt-1 in pregnancies complicated by preeclampsia with and without IUGR

Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.

Maternal serum concentration of soluble fms-like tyrosine kinase 1 and vascular endothelial growth factor in women with abnormal uterine artery Doppler and in those with fetal growth restriction

This study was undertaken to determine whether maternal serum concentration of the angiogenic factor vascular endothelial growth factor (VEGF) and its circulating antagonist, soluble fms-like tyrosine kinase 1 (sFlt-1), which have been implicated in the pathogenesis of preeclampsia (PE), are altered in pregnancies that subsequently develop PE and in those with established fetal growth restriction (FGR). Three groups of healthy pregnant women at 23 to 25 weeks of gestation were examined: group A (n = 42) with normal uterine artery Doppler waveforms, group B (n = 49) with abnormal uterine artery Doppler waveforms, and group C (n = 15) with abnormal Doppler results and established FGR. Comparisons between multiple groups were performed by using 1-way analysis of variance or Kruskal-Wallis test. In group C, compared with group A, the median sFlt-1 was significantly higher (P < .0001) and VEGF was lower (P < .001). Group C included 3 women who had PE develop. In group B, 19 women had a normal outcome, 13 had PE develop, and 17 had FGR develop. There were no significant differences in sFlt-1 levels between any of the subgroups of group B and group A. Maternal serum concentration of sFlt-1 in pregnancies with FGR is increased but this increase is not evident in pregnancies with impaired placentation that subsequently had either FGR or PE develop.