Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. McGinnis R et al. (2017) Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.//////////////////Ten years of anti-vascular endothelial growth factor therapy. Ferrara N et al. (2016) The targeting of vascular endothelial growth factor A (VEGFA), a crucial regulator of both normal and pathological angiogenesis, has revealed innovative therapeutic approaches in oncology and ophthalmology. The first VEGFA inhibitor, bevacizumab, was approved by the US Food and Drug Administration in 2004 for the first-line treatment of metastatic colorectal cancer, and the first VEGFA inhibitors in ophthalmology, pegaptanib and ranibizumab, were approved in 2004 and 2006, respectively. To mark this tenth anniversary of anti-VEGFA therapy, we discuss the discovery of VEGFA, the successes and challenges in the development of VEGFA inhibitors and the impact of these agents on the treatment of cancers and ophthalmic diseases.//////////////////
Oncogene FLT belongs to the src gene family and is related to oncogene ROS . Like other members of this
family, it shows tyrosine protein kinase activity that is important for the control of cell proliferation and differentiation.
Vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases FLK1
and FLT1, are thought to be important for the development of embryonic vasculature.
NCBI Summary:
This gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family. VEGFR family members are receptor tyrosine kinases (RTKs) which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain. This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes. Multiple transcript variants encoding different isoforms have been found for this gene. Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms. The soluble isoforms are associated with the onset of pre-eclampsia.[provided by RefSeq, May 2009]
Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome. Pau E et al. BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a life-threatening condition associated with ovarian stimulation. Its pathophysiology is unknown and its treatment continues to be empirical. Early (E)- and late (L)-OHSS occur in women at risk, though not in all cases. Vascular endothelial growth factor (VEGF) is related to increased vascular permeability in OHSS. We analysed the dynamics of the VEGF system in E- and L-OHSS. METHODS: A prospective cohort of women undergoing IVF-ICSI treatment were divided into groups. E-OHSS: Nonpregnant patients classified as women not at risk (group 1) (n = 11) and patients at risk who did not (group 2) (n = 18) and did (group 3) (n = 8) develop severe OHSS. Blood was drawn on the day of ovum retrieval (day 0) and 3, 6, 10 and 14 days later. L-OHSS: Single pregnancies classified as women who did not (group 4) (n = 8) and did develop (group 5) (n = 4) OHSS. Single pregnancies after oocyte donation (OD) (n = 4) were compared with groups 4 and 5 (IVF-ICSI). Blood was obtained weekly (weeks 4-12). Total VEGF (VEFG-A), free (f)-VEGF and soluble VEGF receptor 1 (sVEGFR-1) in plasma and in serum alpha2-macroglobulin (M) were also measured. RESULTS: Group 3 showed significantly (P < 0.05) higher VEFG-A and f-VEGF than group 1 on day 6 because of lower sVEGFR-1 secretion. Similarly, group 5 had significantly (P < 0.05) more VEFG-A and f-VEGF and less sVEGFR-1 than group 4. Oocyte donation was associated with decreased sVEGFR-1 secretion, and alpha2M was not relevant in OHSS development. CONCLUSION: In E- and L-OHSS, the ability to secrete sVEGFR-1 and bind VEGF seems to be the determinant factor in OHSS. f-VEGF acts locally in the ovary.
Gene whose expression is detected by cDNA array hybridization: oncogenes, tumor
suppressors, cell cycle regulators Rozenn Dalbi?Tran and Pascal Mermilloda
Expression regulated by
Growth Factors/ cytokines
Comment
Vascular endothelial growth factor-induced expression of its receptors and activation of the MAPK signaling pathway during ovine oocyte maturation in vitro. Yan L et al. The vascular endothelial growth factor (VEGF) has beneficial effects on ovine oocytes during in vitro maturation and their subsequent early embryonic development, but the biochemical pathway underlying this effect has not been elucidated. Therefore, the focus of the present study was to investigate the activation of the mitogen-activated protein kinase (MAPK) pathway in response to the addition of VEGF to the maturation medium, and to study the subcellular localization of VEGF and its receptors during ovine oocyte maturation. We concluded that: (1) VEGF mainly localized in the cytoplasm, whereas its receptors, fms-tyrosine kinase-1 and kinase domain region (KDR), were localized on the plasma membrane of oocytes; (2) the addition of 5 ng/mL VEGF increased the percentage of oocytes with extruded first polar bodies (50.9 2.2% vs. 34.6 2.9%; treatment vs. control, respectively; P < 0.01) and the rate of oocytes competent to undergo nuclear maturation (70.6 0.9% vs. 62.9 1.9%, P < 0.01); and (3) as the expression of VEGF, fms-tyrosine kinase-1, and KDR increased after supplementation with 5 ng/mL, expression of VEGF, mitogen-activated protein kinase kinase (MEK), and MAPK mRNA, as well as MAPK phosphorylation, were stimulated in a time-dependent manner. We inferred that, in a paracrine manner, exogenous VEGF bound to KDR, its main receptor, and then activated the MAPK signaling pathway, which promoted maturation of ovine oocytes. However, the VEGF system also had an autocrine regulatory loop that contributed to creating an environment optimal for oocyte maturation.
Ovarian localization
Oocyte
Comment
Yoshinori Okamura et al 2001 reported the protein tyrosine kinase expression in the porcine ovary.
Various growth factor receptors contain intrinsic tyrosine kinase activity, indicating that protein tyrosine kinases (PTK)
play an important role in signal transduction pathways for cell proliferation and differentiation. To identify
oocyte-derived factors which control follicle cells as well as oocyte-controlling factors produced by follicle cells, the authors
examined the expression of genes which contain the PTK domain in the porcine ovary, using a polymerase chain
reaction-based amplification technique with degenerate oligonucleotide primers that are specific to the PTK domain.
Clones for the porcine
homologues of focal adhesion kinase (FAK), of c-kit and of fms-like tyrosine kinase (FLT)-3 were found only in
oocytes. Moreover, after 24 h of in-vitro maturation of the cumulus-oocyte complexes, clones for the porcine
homologues of FLT-1, of FLT-4, of Tie2 and of RYK in oocytes were observed.