Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, University of Bristol, School of Veterinary Sciences, Bristol, UK.
BJOG. 2011 Sep;118(10):1253-61. doi: 10.1111/j.1471-0528.2011.02925.x. Epub 2011 Jun 14.
Pre-eclampsia is diagnosed by hypertension and proteinuria, probably caused by endothelial dysfunction, resulting in symptoms including oedema, inflammation and altered metabolism. Vascular endothelial growth factor A (VEGF-A) is detected at higher concentrations in plasma from patients with pre-eclampsia than in plasma from normotensive pregnant patients when determined by radioimmunoassay. This study tested the hypothesis that circulating VEGF-A in pre-eclamptic plasma is biologically active in vivo, and aimed to identify specific isoforms responsible for this activity.
Plasma from pre-eclamptic (n = 17) and normotensive (n = 10) pregnant women was perfused into Rana mesenteric microvessels, and the subsequent change in microvascular permeability was measured using a single-vessel perfusion micro-occlusion technique.
Pre-eclamptic but not normotensive plasma resulted in a 5.25 ± 0.8-fold acute increase in vascular permeability (P = 0.0003). This increase could be blocked by the incubation of plasma with bevacizumab, an antibody to VEGF-A (n = 7; P = 0012), and by VEGF-A receptor inhibition by SU5416 at doses specific to VEGF-A receptor-1 (VEGFR1), but not by the VEGF-A receptor-2 inhibitor, ZM323881. Although VEGF(165) b levels were not significantly altered in the PET samples, the increase in permeability was also inhibited by incubation of pre-eclamptic plasma with an inhibitory monoclonal antibody specific for VEGF₁₆₅b (n=6; P<0.01), or by the addition of placental growth factor 1 (PlGF-1; n = 3; P < 0.001). PlGF-1 was detected at lower concentrations in pre-eclamptic plasma than in normotensive plasma.
These findings suggest that circulating VEGF-A levels in pre-eclampsia are biologically active because of a loss of repression of VEGFR1 signalling by PlGF-1, and VEGF₁₆₅b may be involved in the increased vascular permeability of pre-eclampsia.
子痫前期的诊断标准为高血压和蛋白尿，其可能由血管内皮功能障碍引起，导致水肿、炎症和代谢改变等症状。放射免疫测定法检测发现，与正常妊娠孕妇的血浆相比，子痫前期患者的血浆中血管内皮生长因子 A（VEGF-A）浓度更高。本研究旨在验证子痫前期患者血浆中循环 VEGF-A 具有体内生物活性的假设，并确定负责这种活性的特定同工型。
将子痫前期（n = 17）和正常妊娠（n = 10）孕妇的血浆分别灌注到蛙肠系膜微血管中，然后使用单血管灌注微闭塞技术测量微血管通透性随后的变化。
子痫前期患者的血浆而非正常妊娠患者的血浆会导致血管通透性急性增加 5.25 ± 0.8 倍（P = 0.0003）。这种增加可以通过用贝伐单抗（bevacizumab）孵育血浆来阻断，贝伐单抗是一种针对 VEGF-A 的抗体（n = 7；P = 0012），也可以通过 SU5416 抑制 VEGF-A 受体来阻断，SU5416 是一种针对 VEGF-A 受体-1（VEGFR1）的特异性抑制剂，但不能通过 VEGF-A 受体-2 抑制剂 ZM323881 来阻断。虽然 PET 样本中 VEGF(165)b 水平没有明显改变，但孵育子痫前期患者的血浆与针对 VEGF₁₆₅b 的抑制性单克隆抗体（n = 6；P<0.01），或添加胎盘生长因子 1（PlGF-1；n = 3；P < 0.001）也可抑制通透性增加。PlGF-1 在子痫前期患者的血浆中的浓度低于正常妊娠患者的血浆。
这些发现表明，子痫前期患者循环 VEGF-A 水平具有生物活性，因为 PlGF-1 失去了对 VEGFR1 信号的抑制作用，而 VEGF₁₆₅b 可能参与了子痫前期患者的血管通透性增加。
