Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Rheumatology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
J Cell Physiol. 2019 Jul;234(7):10184-10195. doi: 10.1002/jcp.27688. Epub 2018 Nov 1.
During pregnancy, a tremendous increase in fetoplacental angiogenesis is associated with elevated blood flow. Aberrant fetoplacental vascular function may lead to pregnancy complications including pre-eclampsia. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are crucial regulators of fetoplacental endothelial function. G protein α subunit 14 (GNA14), a member of Gαq/11 subfamily is involved in mediating hypertensive diseases and tumor vascularization. However, little is known about roles of GNA14 in mediating the FGF2- and VEGFA-induced fetoplacental endothelial function. Using human umbilical vein endothelial cells (HUVECs) cultured under physiological chronic low oxygen (3% O ) as a cell model, we show that transfecting cells with adenovirus carrying GNA14 complementary DNA (cDNA; Ad-GNA14) increases (p < 0.05) protein expression of GNA14. GNA14 overexpression blocks (p < 0.05) FGF2-stimulated endothelial migration, whereas it enhances (p < 0.05) endothelial monolayer integrity (maximum increase of ~35% over the control at 24 hr) in response to FGF2. In contrast, GNA14 overexpression does not significantly alter VEGFA-stimulated cell migration, VEGFA-weakened cell monolayer integrity, and intracellular Ca mobilization in response to adenosine triphosphate (ATP), FGF2, and VEGFA. GNA14 overexpression does not alter either FGF2- or VEGFA-induced phosphorylation of ERK1/2. However, GNA14 overexpression time-dependently elevates (p < 0.05) phosphorylation of phospholipase C-β3 (PLCβ3) at S1105 in response to FGF2, but not VEGFA. These data suggest that GNA14 distinctively mediates fetoplacental endothelial cell migration and permeability in response to FGF2 and VEGFA, possibly in part by altering activation of PLCβ3 under physiological chronic low oxygen.
在妊娠期间，胎盘中血管生成的大量增加与血流增加有关。胎盘中血管功能异常可能导致包括先兆子痫在内的妊娠并发症。成纤维细胞生长因子 2（FGF2）和血管内皮生长因子 A（VEGFA）是胎盘中内皮功能的关键调节因子。G 蛋白α亚单位 14（GNA14）是 Gαq/11 亚家族的成员，参与介导高血压疾病和肿瘤血管生成。然而，目前对于 GNA14 在介导 FGF2 和 VEGFA 诱导的胎盘中内皮功能中的作用知之甚少。我们使用在生理慢性低氧（3% O ）下培养的人脐静脉内皮细胞（HUVECs）作为细胞模型，结果表明，用携带 GNA14 互补 DNA（cDNA；Ad-GNA14）的腺病毒转染细胞会增加 GNA14 的蛋白表达（p<0.05）。GNA14 的过表达会阻断（p<0.05）FGF2 刺激的内皮细胞迁移，而增强（p<0.05）内皮单层完整性（在 24 小时时相对于对照增加约 35%）对 FGF2 的反应。相反，GNA14 的过表达不会显著改变 VEGFA 刺激的细胞迁移、VEGFA 减弱的细胞单层完整性以及对三磷酸腺苷（ATP）、FGF2 和 VEGFA 的细胞内 Ca 动员。GNA14 的过表达也不会改变 FGF2 或 VEGFA 诱导的 ERK1/2 磷酸化。然而，GNA14 的过表达会随时间推移（p<0.05）增加对 FGF2 的反应中磷脂酶 C-β3（PLCβ3）的 S1105 磷酸化，但不会增加对 VEGFA 的反应。这些数据表明，GNA14 独特地介导胎盘中内皮细胞对 FGF2 和 VEGFA 的迁移和通透性，可能部分是通过改变生理慢性低氧下 PLCβ3 的激活来实现的。
