Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1

Banks, Rosamonde E.; Forbes, M A; Searles, Jackson; Pappin, Darryl; Cañas, Benito; Rahman, Dinah; Kaufmann, Scott H.; Walters, Christian; Jackson, Anthony; Eves, Paula; Linton, G.; Keen, James H.; Walker, James J.; Selby, Peter J.

doi:10.1093/molehr/4.4.377

Cited by 109 publications

(63 citation statements)

References 64 publications

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“…free VEGF and free PlGF (22,23). We first confirmed that these ELISA kits measured only unbound VEGF or PlGF by performing a standard curve for VEGF and PlGF proteins in the presence of exogenous recombinant sFlt1.…”

Section: Figurementioning

confidence: 73%

“…Several authors have reported increased systemic VEGF levels in women with preeclampsia (31-34) while other authors have reported decreased levels (35-37), as we report here (Figure 2c). In reviewing the methodology of these studies carefully, we found that all studies reporting decreased VEGF (35-37) used a commercially available ELISA kit (R&D Systems), which, in fact, measures free (unbound) VEGF as previously shown by others (22,23,38). All studies reporting increased VEGF in preeclampsia used either radioimmunoassay or a non-R&D ELISA system, measuring total (bound and unbound) VEGF (31)(32)(33)(34).…”

Section: Figurementioning

confidence: 94%

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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Maynard¹,

Jiang²,

Merchan³

et al. 2003

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Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

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Section: Figurementioning

confidence: 73%

Section: Figurementioning

confidence: 94%

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Maynard¹,

Jiang²,

Merchan³

et al. 2003

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“…The effects on NF-B activation on angiogenesis in the placenta are not well understood. HIF-1␣, VEGF, VEGF receptors, and TIE-2 have been detected on trophoblasts and endothelial cells (22,(37)(38)(39). The mRNA levels of VEGF and VEGF receptors were dependent on gestational age and mode of delivery, but no analysis of chorioamnionitis was included (38).…”

Section: Discussionmentioning

confidence: 99%

“…In brief, after incubation with rabbit anti-human NF-B, an HRP-conjugated goat-anti-rabbit Capillaries that were stained along the circumference were recorded as positive. VEGF, VEGF-R1, VEGF-R2, TIE-2, and HIF-1␣ were expressed on all endothelial cells (22,(37)(38)(39). Therefore, the intensity of staining was measured with a three-step semiquantitative scale (magnification ϫ200) as weak (ϩ1), moderate (ϩ2), or strong (ϩ3) (40)…”

Section: Methodsmentioning

confidence: 99%

Decreased Expression of Angiogenic Factors in Placentas with Chorioamnionitis after Preterm Birth

et al. 2005

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Chorioamnionitis and funisitis are associated with neonatal morbidity and mortality. We hypothesized that chorioamnionitis may stress fetal endothelium, activate proinflammatory gene transcription. and affect angiogenic homeostasis in fetal capillaries. Placentas from preterm infants were stained for heat-shock protein 70, nuclear factor-B, hypoxia-inducible factor-1␣, and vascular endothelial growth factor (VEGF). VEGF receptors (VEGF-R) 1 and 2 as well as the receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE-2), which is involved in vascular remodeling, were quantified. Immunohistochemistry was analyzed by counting positive capillaries in placental terminal villi. Staining intensity was quantified by a three-step semiquantitative scale. The samples were divided into three matched groups according to histology: chorioamnionitis with funisitis ("funisitis"), chorioamnionitis without funisitis ("chorioamnionitis"), and control group with no inflammation. In tissues from the funisitis or chorioamnionitis group, heat-shock protein 70 expression was increased over the control group. More nuclear factor-B-positive nuclei of endothelial cells in capillaries were counted in the funisitis and chorioamnionitis groups. Expression of VEGF and VEGF-R1 and -R2 were reduced in cases of funisitis or chorioamnionitis in comparison with controls. Hypoxia-inducible factor-1␣ expression tended to be slightly lower in the funisitis and chorioamnionitis groups but did not reach statistical significance. We speculate that cellular stress and changes in angiogenic homeostasis induced by proinflammatory activation of fetal endothelium in chorioamnionitis may not be limited to the placenta but may also involve other fetal organs. (Pediatr Res 58: 607-612, 2005) Abbreviations BPD, bronchopulmonary dysplasia CI, confidence interval HIF-1␣ hypoxia-inducible factor-1␣ HRP, horseradish peroxidase HSP70, heat-shock protein 70 IL, interleukin NF-B, nuclear factor-B TIE-2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 VEGF, vascular endothelial growth factor VEGF-R, vascular endothelial growth factor receptor Chorioamnionitis is very common in preterm birth (1). Microbial infection of the amnion and chorion are detected in 60% of all preterm deliveries (2). Funisitis is diagnosed as an infiltration of neutrophils in the umbilical cord vessels (3) and can be considered as a progression of chorioamnionitis with systemic inflammatory response syndrome of the fetus (4). Although fetal inflammation reduces the incidence of respiratory distress syndrome (5,6) and increases the survival of preterm infants (7), the fetal inflammatory response has been associated with increased neonatal morbidity. The mechanisms by which fetal inflammation increases the incidence of bronchopulmonary dysplasia (BPD) (8), retinopathy of prematurity (9), intracranial hemorrhage (10), cerebral palsy, and adverse neurodevelopmental outcome (11-13) are not fully understood. Recently, a new poten...

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“…In fact, at least part of the dilator response to VEGF has been ascribed to induction of nitric oxide (NO) release (10). Of interest, a soluble form of VEGFR1 also exists; it is secreted by endothelial cells and was shown to inhibit VEGF activity in vitro by sequestering the ligand (1,(11)(12)(13).…”

mentioning

confidence: 99%

Changes in Expression of Vascular Endothelial Growth Factor and Its Receptors in Neonatal Hypoxia-Induced Pulmonary Hypertension

et al. 2005

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Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1

Cited by 109 publications

References 64 publications

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Decreased Expression of Angiogenic Factors in Placentas with Chorioamnionitis after Preterm Birth

Changes in Expression of Vascular Endothelial Growth Factor and Its Receptors in Neonatal Hypoxia-Induced Pulmonary Hypertension

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