Department of Obstetrics, Gynecology, and Reproductive Sciences and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland.
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia.
Am J Physiol Heart Circ Physiol. 2021 Apr 1;320(4):H1712-H1723. doi: 10.1152/ajpheart.00613.2020. Epub 2021 Mar 5.
Uterine spiral artery remodeling (UAR) is essential for placental perfusion and fetal development. A defect in UAR underpins placental ischemia disorders, e.g., preeclampsia, that result in maternal systemic vascular endothelial dysfunction and hypertension. We have established a model of impaired UAR by prematurely elevating maternal serum estradiol levels during the first trimester of baboon pregnancy. However, it is unknown whether this experimental paradigm is associated with maternal vascular endothelial dysfunction. Therefore, in the present study baboons were administered estradiol on of gestation to suppress UAR and maternal vascular function determined on (term = 184 days) peripherally and in skeletal muscle, which accounts for over 40% of body mass and 25% of resting systemic vascular resistance. Maternal serum sFlt-1 levels were 2.5-fold higher ( < 0.05), and skeletal muscle arteriolar endothelial nitric oxide synthase (eNOS) protein expression and luminal area, and skeletal muscle capillary density were 30-50% lower ( < 0.05) in UAR suppressed baboons. Coinciding with these changes in eNOS expression, luminal area, and capillary density, maternal brachial artery flow-mediated dilation and volume flow were 70% and 55% lower ( < 0.05), respectively, and mean arterial blood pressure 29% higher ( < 0.01) in UAR defective baboons. In summary, maternal vascular function was disrupted in a baboon model of impaired UAR. These results highlight the translational impact of this primate model and relevance to adverse conditions of human pregnancy underpinned by improper uterine artery transformation. Maternal vascular dysfunction is a hallmark of abnormal human pregnancy, particularly early-onset preeclampsia, elicited by impaired UAR. The present study makes the novel discovery that maternal systemic vascular dysfunction was induced in a baboon experimental model of impaired UAR. This study highlights the translational relevance of this nonhuman primate model to adverse conditions of human pregnancy underpinned by defective UAR.
子宫螺旋动脉重塑（UAR）对于胎盘灌注和胎儿发育至关重要。UAR 缺陷是胎盘缺血性疾病的基础，例如先兆子痫，导致母体全身血管内皮功能障碍和高血压。我们已经通过在狒狒妊娠的第一个三个月提前升高母体血清雌二醇水平建立了 UAR 受损的模型。然而，尚不清楚这种实验模型是否与母体血管内皮功能障碍有关。因此，在本研究中，在妊娠的第 天给狒狒注射雌二醇以抑制 UAR，并在第 天（足月= 184 天）通过外周和骨骼肌来确定母体血管功能，骨骼肌占体重的 40%以上，占静息全身血管阻力的 25%。UAR 受抑制的狒狒的母体血清 sFlt-1 水平高 2.5 倍（<0.05），骨骼肌小动脉内皮型一氧化氮合酶（eNOS）蛋白表达和管腔面积以及骨骼肌毛细血管密度降低 30-50%（<0.05）。与 eNOS 表达、管腔面积和毛细血管密度的这些变化一致，UAR 缺陷的狒狒的母体肱动脉血流介导的扩张和体积流量分别降低 70%和 55%（<0.05），平均动脉血压升高 29%（<0.01）。总之，在 UAR 受损的狒狒模型中，母体血管功能受到破坏。这些结果突出了这种灵长类动物模型的转化影响及其与子宫动脉转化不当为基础的人类妊娠不良条件的相关性。母体血管功能障碍是异常人类妊娠的标志，特别是由 UAR 受损引起的早发型先兆子痫。本研究的新发现是，在 UAR 受损的狒狒实验模型中诱导了母体全身血管功能障碍。本研究强调了这种非人类灵长类动物模型与 UAR 缺陷为基础的人类妊娠不良条件的转化相关性。
