Structure and function of VEGF receptors related to preeclampsia.

子痫前期是妇科的主要疾病。近年来的研究表明，可溶性Flt-1（sFlt-1/sVEGFR 1）与该病密切相关。我们试图了解Flt-1蛋白包括sFlt-1.1的全部功能。我们发现滋养层干细胞（trophoblast stem cell，TS细胞）系统可以作为Flt-1基因表达的良好模型，因为在胎盘中，滋养层细胞是sFlt-1的主要生产者。在分化过程中，flt-1 mRNA升高5倍，表明生理基因表达。然而，我们没有发现异常上调sflt-l表达的应激。研究了外源性VEGF-A和sFlt-1对妊娠小鼠的影响。我们发现外源性VEGF-A可引起胎盘组织病理变化，如纤维蛋白沉积，外源性sFlt-1可引起一过性高血压和蛋白尿。然而，为了维持这些表型，似乎需要大量的sFlt-1。3，sFlt-1蛋白有效地阻断腹水肿瘤异常分泌的VEGF-A，导致腹水体积和腹水中肿瘤生长的抑制。因此，sFlt-1蛋白是病理性VEGF-A和腹水肿瘤抑制剂的良好候选物。（Flt-1 TK-/-小鼠）在关节炎模型中表现出较温和的表型，表明Flt-1的酪氨酸激酶是治疗类风湿关节炎的新靶点。Ambati博士的小组与我们合作发现sFlt-1- 1是维持角膜无血管性的重要天然分子。

Preeclampsia is a major disease in gynecological field. Recent studies strongly suggest that soluble form of Flt-1 (sFlt-1/sVEGFR1) is deeply involved in this disease. We attempted to understand the whole functions of Flt-1 protein including sFlt-1.1, We found that trophoblast stem cell (TS cell) system could be a good model for flt-1 gene expression, since in placenta, trophoblast cells are the major producer for sFlt-1. During the differentiation, flt-1 mRNA was 5-fold elevated, suggesting a physiological gene expression. However, we could not find a stress which abnormally upregulate the expression of sflt-l. Such a stress could be a candidate for inducer of preeclampsia.2, We examined the effect of exogenous VEGF-A and sFlt-1 on pregnant mice. We found that exogenous VEGF-A induces pathological change at placenta such as fibrin deposition, and exogenous sFlt-1 transiently induces hypertension and proteinurea. However, to maintain these phenotypes, a large amount of sFlt-1 appears to be required.3, sFlt-1 protein efficiently blocked abnormally secreted VEGF-A from ascites tumors, resulting in suppression of ascites volume and tumor growth in ascites. Thus, sFlt-1 protein is a good candidate for an inhibitor of pathological VEGF-A and ascites tumor.4, Flt-1 signaling-deficient mice (Flt-1 TK-/- mice) showed a milder phenotype in arthritis-model, indicating that tyrosine kinase of Flt-1 is a new target for the treatment of rheumatoid arthritis.Dr.Ambati' s group collaborating with us found that sFlt-1 is an important natural molecule for maintaining avascularity in cornea.