OC15.02: Increased levels of soluble FMS‐like tyrosine kinase‐1 are associated with adverse outcomes in pregnant women with COVID‐19
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SUBMITTER: Torres‐Torres J
PROVIDER: S-EPMC8661635 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF).Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined.We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years.The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes.Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.
| S-EPMC3193932 | biostudies-literature
Project description:Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.
| S-EPMC4922717 | biostudies-literature
Project description:IntroductionSoluble fms-like tyrosine kinase 1 (sFLT1) is a splice variant of the vascular endothelial growth factor (VEGF) receptor lacking the transmembrane and cytoplasmic domains and acts as a powerful antagonist of VEGF signaling. Plasma sFLT1 levels are higher in patients with chronic kidney disease (CKD) and correlate with renal dysfunction. The source of plasma sFLT1 in CKD is unclear.MethodsFifty-two renal biopsies were studied for sFLT1 expression using immunohistochemistry and evaluated on a 0-4 grading scale of positive cells within inflammatory infiltrates. These included drug-induced interstitial nephritis (6); allografts (12), with polyomavirus nephritis (3); diabetes mellitus (10); lupus glomerulonephritis (6); pauci-immune vasculitis (7); IgA nephropathy (6); and miscellaneous CKD (5).ResultsForty-seven biopsies had inflammatory infiltrates of which 37 had sFLT1-positive cells: of these biopsies, 3 were grade 4, i.e., had cells that constituted more than 50% of the inflammatory infiltrate, 9 were grade 3 (25%-50%), 5 were grade 2 (10%-25%), 3 were grade 1 (10%), and 17 were grade 0.5 (<10%). There was a robust correlation (r2 = 0.89) between degree of inflammation and sFLT1-positive cells. CD68/sFLT1 co-immunostaining studies indicated that sFLT1-positive cells were histiocytes. The surrounding capillary network was reduced.ConclusionsFLT1-positive histiocytes are generally part of the inflammatory infiltrates noted in CKD and are particularly abundant in forms of interstitial nephritis. Their presence promotes an anti-angiogenic state locally in the tubulointerstitium that could inhibit capillary repair, contribute to peritubular capillary loss, and enhance fibrosis in CKD.
| S-EPMC6895657 | biostudies-literature
Project description:Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasma-specific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20-38 years of age) with very preterm preeclampsia (23-32 weeks of gestation, systolic BP ?140 mmHg or diastolic BP ?90 mmHg, new onset protein/creatinine ratio >0.30 g/g, and sFlt-1/placental growth factor ratio >85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%-28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2-11) and 15 days (range 11-21) in women treated once and multiple times, respectively, compared with 3 days (range 0-14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.
| S-EPMC4769204 | biostudies-literature
Project description:Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.
| S-EPMC5845757 | biostudies-literature
Project description:Soluble fms-like tyrosine kinase-1 (sFlt-1) is a secreted protein that binds heparan sulfate expressed on the endothelial glycocalyx (eGC). In this paper we analyze how excess sFlt-1 causes conformational changes in the eGC, leading to monocyte adhesion, a key event triggering vascular dysfunction. In vitro exposure of primary human umbilical vein endothelial cells to excess sFlt-1 decreased eGC height and increased stiffness as determined by atomic force microscopy (AFM). Yet, structural loss of the eGC components was not observed, as indicated by Ulex europaeus agglutinin I and wheat germ agglutinin staining. Moreover, the conformation observed under excess sFlt-1, a collapsed eGC, is flat and stiff with unchanged coverage and sustained content. Functionally, this conformation increased the endothelial adhesiveness to THP-1 monocytes by about 35%. Heparin blocked all these effects, but the vascular endothelial growth factor did not. In vivo administration of sFlt-1 in mice also resulted in the collapse of the eGC in isolated aorta analyzed ex vivo by AFM. Our findings show that excess sFlt-1 causes the collapse of the eGC and favors leukocyte adhesion. This study provides an additional mechanism of action by which sFlt-1 may cause endothelial dysfunction and injury.
| S-EPMC10049398 | biostudies-literature
Project description: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.
| S-EPMC3266823 | biostudies-literature
Project description:Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models.We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (? 280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (? 25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF.Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.
| S-EPMC4692173 | biostudies-literature
Project description:To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.
| S-EPMC9566901 | biostudies-literature
Project description:We sought to assess the ratio of sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor) in maternal serum as a screening test for preeclampsia in unselected nulliparous women with a singleton pregnancy. We studied 4099 women recruited to the POP study (Pregnancy Outcome Prediction) (Cambridge, United Kingdom). The sFlt-1:PlGF ratio was measured using the Roche Cobas e411 platform at ?20, ?28, and ?36 weeks of gestational age (wkGA). Screen positive was defined as an sFlt-1:PlGF ratio >38, but higher thresholds were also studied. At 28 wkGA, an sFlt-1:PlGF ratio >38 had a positive predictive value (PPV) of 32% for preeclampsia and preterm birth, and the PPV was similar comparing women with low and high prior risk of disease. At 36 wkGA, an sFlt-1:PlGF ratio >38 had a PPV for severe preeclampsia of 20% in high-risk women and 6.4% in low-risk women. At 36 wkGA, an sFlt-1:PlGF ratio >110 had a PPV of 30% for severe preeclampsia, and the PPV was similar comparing low- and high-risk women. Overall, at 36 wkGA, 195 (5.2%) women either had an sFlt-1:PlGF ratio of >110 or an sFlt-1:PlGF ratio >38 plus maternal risk factors: 43% of these women developed preeclampsia, about half with severe features. Among low-risk women at 36 wkGA, an sFlt-1:PlGF ratio ?38 had a negative predictive value for severe preeclampsia of 99.2%. The sFlt-1:PlGF ratio provided clinically useful prediction of the risk of the most important manifestations of preeclampsia in a cohort of unselected nulliparous women.
| S-EPMC5344177 | biostudies-literature