Ahmad Shakil, Hewett Peter W, Al-Ani Bahjat, Sissaoui Samir, Fujisawa Takeshi, Cudmore Melissa J, Ahmed Asif
University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Department of Reproductive and Vascular Biology, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
Vasc Cell. 2011 Jul 13;3(1):15. doi: 10.1186/2045-824X-3-15.
The negative feedback system is an important physiological regulatory mechanism controlling angiogenesis. Soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), acts as a potent endogenous soluble inhibitor of VEGF- and placenta growth factor (PlGF)-mediated biological function and can also form dominant-negative complexes with competent full-length VEGF receptors.
Systemic overexpression of VEGF-A in mice resulted in significantly elevated circulating sFlt-1. In addition, stimulation of human umbilical vein endothelial cells (HUVEC) with VEGF-A, induced a five-fold increase in sFlt-1 mRNA, a time-dependent significant increase in the release of sFlt-1 into the culture medium and activation of the flt-1 gene promoter. This response was dependent on VEGF receptor-2 (VEGFR-2) and phosphoinositide-3'-kinase signalling. siRNA-mediated knockdown of sFlt-1 in HUVEC stimulated the activation of endothelial nitric oxide synthase, increased basal and VEGF-induced cell migration and enhanced endothelial tube formation on growth factor reduced Matrigel. In contrast, adenoviral overexpression of sFlt-1 suppressed phosphorylation of VEGFR-2 at tyrosine 951 and ERK-1/-2 MAPK and reduced HUVEC proliferation. Preeclampsia is associated with elevated placental and systemic sFlt-1. Phosphorylation of VEGFR-2 tyrosine 951 was greatly reduced in placenta from preeclamptic patients compared to gestationally-matched normal placenta.
These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function.
负反馈系统是控制血管生成的重要生理调节机制。可溶性血管内皮生长因子（VEGF）受体-1（sFlt-1）是VEGF和胎盘生长因子（PlGF）介导的生物学功能的有效内源性可溶性抑制剂，还可与有活性的全长VEGF受体形成显性负性复合物。
小鼠体内VEGF-A的系统性过表达导致循环中sFlt-1显著升高。此外，用VEGF-A刺激人脐静脉内皮细胞（HUVEC），可使sFlt-1 mRNA增加5倍，sFlt-1释放到培养基中的量随时间显著增加，且flt-1基因启动子被激活。这种反应依赖于VEGF受体-2（VEGFR-2）和磷酸肌醇-3'-激酶信号传导。siRNA介导的HUVEC中sFlt-1的敲低刺激了内皮型一氧化氮合酶的激活，增加了基础和VEGF诱导的细胞迁移，并增强了在生长因子减少的基质胶上的内皮管形成。相反，腺病毒介导的sFlt-1过表达抑制了VEGFR-2在酪氨酸951处的磷酸化以及ERK-1/-2 MAPK，并降低了HUVEC的增殖。子痫前期与胎盘和全身sFlt-1升高有关。与妊娠匹配的正常胎盘相比，子痫前期患者胎盘中VEGFR-酪氨酸951的磷酸化显著降低。
这些结果表明内皮细胞sFlt-1的表达受VEGF调节，并作为内皮细胞功能的自分泌调节因子发挥作用。
