Brownbill P, McKeeman G C, Brockelsby J C, Crocker I P, Sibley C P
University Research Floor, St. Mary's Hospital, Hathersage Road, Manchester, United Kingdom.
Endocrinology. 2007 Oct;148(10):4734-44. doi: 10.1210/en.2007-0180. Epub 2007 Jul 19.
Vascular endothelial growth factor (VEGF) is an important vasodilator and effector of permeability in systemic blood vessels. Molecular and tissue culture techniques have provided evidence for its placental synthesis and release. Using an in vitro dual-perfusion model of the term placental lobule from normal pregnancy, we report here the relative secretion of total VEGF, soluble VEGF receptor (VEGFR)-1, and free VEGF into the maternal and fetoplacental circulations of the placenta. We tested the hypothesis that VEGF has vasomotor and permeability effects in the fetoplacental circulation of the human placenta, and we examined the broad intracellular pathways involved in the vasodilatory effect that we found. We show that total VEGF is released into the fetal and maternal circulations in a bipolar fashion, with a bias toward maternal side output. Soluble VEGFR-1 was also secreted into both circulations with bias toward the maternal side. Consequently, free VEGF (12.8 +/- 2.4 pg/ml, mean +/- se) was found only in the fetoplacental circulation. VEGF-165 was found to be a potent vasodilator of the fetoplacental circulation (maximum response: 77% of previous steady-state fetal-side inflow hydrostatic pressure after preconstriction with U46619; EC(50) = 71 pm). This vasodilatory effect was mediated by the VEGFR-2 receptor and nitric oxide in a manner-independent of the involvement of prostacyclin and the src-family tyrosine kinases. However, nitric oxide could explain only 50% of the vasodilatory effect. Finally, we measured the permeability of the perfused placenta to inert hydrophilic tracers and found no difference in the presence and absence of VEGF.
血管内皮生长因子（VEGF）是全身血管中一种重要的血管舒张剂和通透性调节因子。分子和组织培养技术已证实其在胎盘的合成与释放。我们利用正常妊娠足月胎盘小叶的体外双灌注模型，报告了胎盘母体和胎儿 - 胎盘循环中总VEGF、可溶性VEGF受体（VEGFR）-1和游离VEGF的相对分泌情况。我们验证了VEGF在人胎盘胎儿 - 胎盘循环中具有血管舒缩和通透性作用这一假说，并研究了我们所发现的血管舒张作用涉及的广泛细胞内信号通路。我们发现，总VEGF以双极方式释放到胎儿和母体循环中，且偏向于母体侧输出。可溶性VEGFR - 1也分泌到两个循环中，同样偏向于母体侧。因此，仅在胎儿 - 胎盘循环中发现了游离VEGF（12.8±2.4 pg/ml，平均值±标准误）。VEGF - 165被发现是胎儿 - 胎盘循环的一种强效血管舒张剂（最大反应：在用U46619预收缩后，为先前稳态胎儿侧流入静水压力的77%；半数有效浓度（EC50） = 71 pm）。这种血管舒张作用由VEGFR - 2受体和一氧化氮介导，其方式独立于前列环素和src家族酪氨酸激酶的参与。然而，一氧化氮仅能解释50%的血管舒张作用。最后，我们测量了灌注胎盘对惰性亲水性示踪剂的通透性，发现在有和没有VEGF的情况下没有差异。
