Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Studies in Reproduction, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Endocrinology. 2012 Jun;153(6):2897-906. doi: 10.1210/en.2012-1141. Epub 2012 Apr 11.
We previously showed that advancing the increase in estradiol levels from the second to the first third of baboon pregnancy suppressed placental extravillous trophoblast (EVT) invasion and remodeling of the uterine spiral arteries. Cell culture studies show that vascular endothelial cell growth factor (VEGF) plays a central role in regulating EVT migration and remodeling of the uterine spiral arteries by increasing the expression/action of certain integrins that control extracellular matrix remodeling. To test the hypothesis that the estradiol-induced reduction in vessel remodeling in baboons is associated with an alteration in VEGF and integrin expression, extravillous placental VEGF and integrin expression was determined on d 60 of gestation (term is 184 d) in baboons in which uterine artery transformation was suppressed by maternal estradiol administration on d 25-59. EVT uterine spiral artery invasion was 5-fold lower (P < 0.01), and VEGF protein expression, quantified by in situ proximity ligation assay, was 50% lower (P < 0.05) in the placenta anchoring villi of estradiol-treated than in untreated baboons. α1β1 and α5β1 mRNA levels in cells isolated by laser capture microdissection from the anchoring villi and cytotrophoblastic shell of estradiol-treated baboons were over 2-fold (P < 0.01) and 40% (P < 0.05) lower, respectively, than in untreated animals. In contrast, placental extravillous αvβ3 mRNA expression was unaltered by estradiol treatment. In summary, extravillous placental expression of VEGF and α1β1 and α5β1 integrins was decreased in a cell- and integrin-specific manner in baboons in which EVT invasion and remodeling of the uterine spiral arteries were suppressed by prematurely elevating estradiol levels in early pregnancy. We propose that estrogen normally controls the extent to which the uterine arteries are transformed by placental EVT in primate pregnancy by regulating expression of VEGF and particular integrin extracellular remodeling molecules that mediate this process.
我们之前的研究表明，在狒狒妊娠的第二到第一三分之一期间提高雌二醇水平，会抑制胎盘绒毛外滋养细胞（EVT）的入侵和子宫螺旋动脉的重塑。细胞培养研究表明，血管内皮生长因子（VEGF）通过增加某些整合素的表达/作用来调节 EVT 迁移和子宫螺旋动脉重塑，从而在控制细胞外基质重塑中发挥核心作用。这些整合素可以控制细胞外基质重塑。为了检验雌二醇诱导的狒狒血管重塑减少与 VEGF 和整合素表达改变相关的假设，我们在妊娠第 60 天（足月为 184 天）测定了接受雌二醇处理的狒狒的胎盘绒毛外 VEGF 和整合素表达，这些狒狒在妊娠第 25-59 天接受了母体内源性雌二醇治疗，以抑制子宫动脉转化。VEGF 蛋白表达通过原位邻近连接测定进行定量，在接受雌二醇处理的狒狒胎盘附着绒毛中降低了 50%（P < 0.05）。与未处理的狒狒相比，接受雌二醇处理的狒狒的 EVT 子宫螺旋动脉入侵降低了 5 倍（P < 0.01），并且通过激光捕获微切割从附着绒毛和细胞滋养层壳中分离的细胞的α1β1 和α5β1 mRNA 水平分别升高了 2 倍（P < 0.01）和 40%（P < 0.05）。相比之下，胎盘绒毛外αvβ3 mRNA 表达不受雌二醇处理的影响。总之，在过早提高妊娠早期雌二醇水平抑制 EVT 入侵和子宫螺旋动脉重塑的狒狒中，VEGF 和α1β1 和α5β1 整合素的胎盘绒毛外表达以细胞和整合素特异性的方式降低。我们提出，雌激素通过调节 VEGF 和介导该过程的特定整合素细胞外重塑分子的表达，正常控制灵长类妊娠中胎盘 EVT 引起的子宫动脉转化程度。
