Department of Obstetrics and Gynecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.
Am J Physiol Heart Circ Physiol. 2023 Oct 1;325(4):H790-H805. doi: 10.1152/ajpheart.00205.2023. Epub 2023 Aug 4.
Fetal growth throughout pregnancy relies on delivery of an increasing volume of maternal blood to the placenta. To facilitate this, the uterine vascular network adapts structurally and functionally, resulting in wider blood vessels with decreased flow-mediated reactivity. Impaired remodeling of the rate-limiting uterine radial arteries has been associated with fetal growth restriction. However, the mechanisms underlying normal or pathological radial artery remodeling are poorly understood. Here, we used pressure myography to determine the roles of hemodynamic (resistance, flow rate, shear stress) and paracrine [β-estradiol, progesterone, placental growth factor (PlGF), vascular endothelial growth factor] factors on rat radial artery reactivity. We show that β-estradiol, progesterone, and PlGF attenuate flow-mediated constriction of radial arteries from nonpregnant rats, allowing them to withstand higher flow rates in a similar manner to pregnant vessels. This effect was partly mediated by nitric oxide (NO) production. To better understand how the combination of paracrine factors and shear stress may impact human radial artery remodeling in the first half of gestation, computational models of uterine hemodynamics, incorporating physiological parameters for trophoblast plugging and spiral artery remodeling, were used to predict shear stress in the upstream radial arteries across the first half of pregnancy. Human microvascular endothelial cells subjected to these predicted shear stresses demonstrated higher NO production when paracrine factors were added. This suggests that synergistic effects of paracrine and hemodynamic factors induce uterine vascular remodeling and that alterations in this balance could impair radial artery adaptation, limiting blood flow to the placenta and negatively impacting fetal growth. Placenta-specific paracrine factors β-estradiol, progesterone, and placental growth factor attenuate flow-mediated constriction of the rate-limiting uterine radial arteries, enabling higher flow rates in pregnancy. These paracrine factors induce their actions in part via nitric oxide mediated mechanisms. A synergistic combination of paracrine factors and shear stress is likely necessary to produce sufficient levels of nitric oxide during early human pregnancy to trigger adequate uterine vascular adaptation.
妊娠期间胎儿的生长依赖于母体血液不断向胎盘输送。为了实现这一目标，子宫血管网络在结构和功能上进行了适应性改变，导致血管变宽而血流介导的反应性降低。限速性子宫放射状动脉重塑受损与胎儿生长受限有关。然而，正常或病理性放射状动脉重塑的机制尚不清楚。在此，我们使用压力血管造影术来确定血流动力学（阻力、流速、切应力）和旁分泌[β-雌二醇、孕酮、胎盘生长因子（PlGF）、血管内皮生长因子]因素对大鼠放射状动脉反应性的作用。我们表明，β-雌二醇、孕酮和 PlGF 减弱了非妊娠大鼠放射状动脉的血流介导性收缩，使它们能够以与妊娠血管相似的方式承受更高的流速。这种作用部分是通过一氧化氮（NO）的产生来介导的。为了更好地理解旁分泌因子和切应力的组合如何影响妊娠早期人类放射状动脉重塑，我们使用整合了滋养细胞栓子和螺旋动脉重塑的生理参数的子宫血液动力学计算模型，来预测妊娠前半程上游放射状动脉的切应力。将这些预测的切应力施加于人微血管内皮细胞，发现添加旁分泌因子后 NO 的产生增加。这表明旁分泌和血液动力学因素的协同作用诱导了子宫血管重塑，而这种平衡的改变可能会损害放射状动脉的适应性，限制胎盘的血流供应，对胎儿生长产生负面影响。胎盘特异性旁分泌因子β-雌二醇、孕酮和胎盘生长因子减弱了限速性子宫放射状动脉的血流介导性收缩，使妊娠期间能够承受更高的流速。这些旁分泌因子通过一氧化氮介导的机制部分发挥其作用。旁分泌因子和切应力的协同组合可能需要在人类妊娠早期产生足够水平的一氧化氮，以触发足够的子宫血管适应性。
