Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, USA.
Am J Hypertens. 2011 May;24(5):606-12. doi: 10.1038/ajh.2010.247. Epub 2010 Dec 23.
Pre-eclampsia (PE) is a serious hypertensive disorder of pregnancy characterized by excessive production of a soluble form of the vascular endothelial growth factor (VEGF) receptor-1, termed soluble fms-like tyrosine kinase-1 (sFlt-1). This placental-derived factor is believed to be a key contributor to the clinical features of PE. Women with PE are also characterized by the presence of autoantibodies, termed angiotensin type 1 receptor activating autoantibody (AT(1)-AA), that activate the major angiotensin receptor, AT(1). These autoantibodies cause clinical features of PE and elevated sFlt-1 when injected into pregnant mice. The research reported here used this autoantibody-injection model of PE to assess the therapeutic potential of recombinant VEGF(121), a relatively stable form of the natural ligand.
Immunoglobulin G (IgG) from women with PE was injected into pregnant mice with or without continuous infusion of recombinant VEGF(121). Injected mice were monitored for symptoms of PE.
As a result of infusion of recombinant VEGF(121) autoantibody-induced hypertension (systolic blood pressure) was reduced from 159 ± 5 to 124 ± 5 mm Hg, proteinuria from 111 ± 16 to 40 ± 5 mg protein/mg creatinine and blood urea nitrogen levels from 31 ± 1 mg/dl to 18 ± 2 mg/dl, P < 0.05. Histological analysis revealed that autoantibody-induced glomerular damage including the narrowing of Bowman's space and occlusion of capillary loop spaces was largely prevented by VEGF(121) infusion. Finally, impaired placental angiogenesis resulting from AT(1)-AA injection was significantly improved by VEGF(121) infusion.
The infusion of recombinant VEGF(121) significantly attenuated autoantibody-induced features of PE.
子痫前期（PE）是一种严重的妊娠高血压疾病，其特征是大量产生一种可溶性形式的血管内皮生长因子（VEGF）受体-1，称为可溶性 fms 样酪氨酸激酶-1（sFlt-1）。这种胎盘来源的因子被认为是 PE 临床特征的关键贡献者。患有 PE 的女性还具有自身抗体，称为血管紧张素 1 型受体激活自身抗体（AT(1)-AA），该自身抗体激活主要的血管紧张素受体 AT(1)。当将这些自身抗体注入怀孕的小鼠中时，它们会引起 PE 的临床特征和升高的 sFlt-1。本研究使用这种 PE 的自身抗体注射模型来评估重组 VEGF(121)的治疗潜力，重组 VEGF(121)是天然配体的一种相对稳定的形式。
将来自患有 PE 的女性的 IgG 注入怀孕的小鼠中，同时或不连续输注重组 VEGF(121)。监测注射小鼠的 PE 症状。
由于输注重组 VEGF(121)，自身抗体诱导的高血压（收缩压）从 159 ± 5 降至 124 ± 5 mm Hg，蛋白尿从 111 ± 16 降至 40 ± 5 mg 蛋白/mg 肌酐，血尿素氮水平从 31 ± 1 mg/dl 降至 18 ± 2 mg/dl，P < 0.05。组织学分析表明，VEGF(121)输注在很大程度上阻止了自身抗体诱导的肾小球损伤，包括 Bowman 空间变窄和毛细血管环空间闭塞。最后，VEGF(121)输注显著改善了 AT(1)-AA 注射引起的胎盘血管生成受损。
重组 VEGF(121)的输注显著减轻了自身抗体诱导的 PE 特征。
