Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Endocrinology. 2022 Apr 1;163(4). doi: 10.1210/endocr/bqac012.
Uterine spiral artery remodeling (SAR) is essential for promoting placental perfusion and fetal development. A defect in SAR results in placental ischemia and increase in placental expression and serum levels of the soluble fms-like tyrosine kinase-1 (sFlt-1) receptor that binds to and suppresses vascular endothelial growth factor (VEGF) bioavailability, thereby leading to maternal vascular dysfunction. We have established a nonhuman primate model of impaired SAR and maternal vascular dysfunction by prematurely elevating estradiol levels in early baboon pregnancy. However, it is unknown whether this primate model of defective SAR involves an increase in placental expression of sFlt-1, which may suppress VEGF bioavailability and thus SAR in the first trimester. Therefore, to establish the role of sFlt-1 in early pregnancy, SAR was quantified in baboons treated on days 25 through 59 of gestation (term = 184 days) with estradiol or with the sFlt-1 gene targeted selectively to the placental basal plate by ultrasound-mediated/microbubble-facilitated gene delivery technology. Placental basal plate sFlt-1 protein expression was 2-fold higher (P < 0.038) and the level of SAR for vessels > 25 µm in diameter was 72% and 63% lower (P < 0.01), respectively, in estradiol-treated and sFlt-1 gene-treated baboons than in untreated animals. In summary, prematurely elevating estradiol levels or sFlt-1 gene delivery increased placental basal plate sFlt-1 protein expression and suppressed SAR in early baboon pregnancy. This study makes the novel discovery that in elevated levels sFlt-1 has a role both in suppressing SAR in early primate pregnancy and maternal vascular endothelial function in late gestation.
子宫螺旋动脉重塑（SAR）对于促进胎盘灌注和胎儿发育至关重要。SAR 缺陷会导致胎盘缺血和胎盘可溶性 fms 样酪氨酸激酶-1（sFlt-1）受体表达和血清水平增加，该受体与血管内皮生长因子（VEGF）结合并抑制其生物利用度，从而导致母体血管功能障碍。我们通过在早期狒狒妊娠中过早升高雌二醇水平，建立了 SAR 受损和母体血管功能障碍的非人类灵长类动物模型。然而，尚不清楚这种 SAR 缺陷的灵长类动物模型是否涉及胎盘 sFlt-1 表达增加，这可能会抑制 VEGF 的生物利用度，从而影响妊娠早期的 SAR。因此，为了确定 sFlt-1 在妊娠早期的作用，我们在妊娠第 25 至 59 天（足月为 184 天）的雌性狒狒中，用雌二醇或超声介导/微泡辅助基因转染技术靶向胎盘基底板的 sFlt-1 基因，对 SAR 进行了定量检测。与未处理的动物相比，在雌二醇处理和 sFlt-1 基因处理的狒狒中，胎盘基底板 sFlt-1 蛋白表达增加了 2 倍（P＜0.038），直径大于 25μm 的血管 SAR 分别降低了 72%和 63%（P＜0.01）。总之，过早升高雌二醇水平或 sFlt-1 基因转染可增加胎盘基底板 sFlt-1 蛋白表达并抑制早期狒狒妊娠中的 SAR。本研究的新颖之处在于，在升高的水平下，sFlt-1 不仅在抑制早期灵长类妊娠中的 SAR，而且在妊娠晚期抑制母体血管内皮功能方面都发挥了作用。
