The Hemodynamic Basis for Positional- and Inter-Fetal Dependent Effects in Dual Arterial Supply of Mouse Pregnancies

In mammalian pregnancy, maternal cardiovascular adaptations must match the requirements of the growing fetus(es), and respond to physiologic and pathologic conditions. Such adaptations are particularly demanding for mammals bearing large-litter pregnancies, with their inherent conflict between the interests of each individual fetus and the welfare of the entire progeny. The mouse is the most common animal model used to study development and genetics, as well as pregnancy-related diseases. Previous studies suggested that in mice, maternal blood flow to the placentas occurs via a single arterial uterine loop generated by arterial-arterial anastomosis of the uterine artery to the uterine branch of the ovarian artery, resulting in counter bi-directional blood flow. However, we provide here experimental evidence that each placenta is actually supplied by two distinct arterial inputs stemming from the uterine artery and from the uterine branch of the ovarian artery, with position-dependent contribution of flow from each source. Moreover, we report significant positional- and inter-fetal dependent alteration of placental perfusion, which were detected by in vivo MRI and fluorescence imaging. Maternal blood flow to the placentas was dependent on litter size and was attenuated for placentas located centrally along the uterine horn. Distinctive apposing, inter-fetal hemodynamic effects of either reduced or elevated maternal blood flow, were measured for placenta of normal fetuses that are positioned adjacent to either pathological, or to hypovascular Akt1-deficient placentas, respectively. The results reported here underscore the critical importance of confounding local and systemic in utero effects on phenotype presentation, in general and in the setting of genetically modified mice. The unique robustness and plasticity of the uterine vasculature architecture, as reported in this study, can explain the ability to accommodate varying litter sizes, sustain large-litter pregnancies and overcome pathologic challenges. Remarkably, the dual arterial supply is evolutionary conserved in mammals bearing a single offspring, including primates.

在哺乳动物妊娠过程中，母体心血管系统的适应性变化必须适配发育中胎儿的需求，并响应生理与病理状态。此类适应性调整对多胎妊娠的哺乳动物尤为严苛，因每只胎儿的个体利益与整个子代的生存福祉之间存在固有冲突。小鼠（mouse）是研究发育与遗传学、妊娠相关疾病的最常用动物模型。既往研究表明，在小鼠体内，母体向胎盘（placenta）的供血经由单条子宫动脉环路实现：该环路由子宫动脉与卵巢动脉子宫支（uterine branch of the ovarian artery）通过动脉-动脉吻合（arterial-arterial anastomosis）形成，进而产生双向逆流血流。但本研究通过实验证据证实，实际上每个胎盘均由两个独立的动脉供血通路供应：分别源自子宫动脉与卵巢动脉子宫支，且两个来源的血流量占比存在位置依赖性。此外，本研究通过活体磁共振成像（in vivo MRI）与荧光成像（fluorescence imaging）检测到，胎盘灌注状态存在显著的位置依赖性与胎间差异性改变。母体向胎盘的血流量依赖于胎仔数量，沿子宫角居中分布的胎盘其血流量会出现衰减。当正常胎仔的胎盘分别毗邻病理性胎盘或血管减少型Akt1基因缺陷（hypovascular Akt1-deficient）胎盘时，可分别检测到母体血流量降低与升高两种截然不同的反向胎间血流动力学效应。本研究报道的结果强调，无论在整体研究背景下，还是针对基因工程改造小鼠模型时，宫内局部与系统性混杂效应对表型呈现均具有至关重要的影响。本研究揭示的子宫血管架构所特有的稳定性与可塑性，可解释哺乳动物为何能够适配不同的胎仔数量、维持多胎妊娠并克服病理挑战。值得注意的是，这种双动脉供血模式在仅生育单仔的哺乳动物（包括灵长类）中具有进化保守性。