Abstract
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.
Highlights
Pregnancy in mammals requires coordinated adaptation of the systemic maternal cardiovascular system and remodeling of the entire uterine circulation, to assure adequate oxygenation and nutrient delivery to the developing embryo/fetus [1,2,3]
Studies of McLaren and Michie in the late 1950s reported that pregnancy is supported in each of the two uterine horns by a single uterine arterial loop, which is generated by direct artery-to-artery anastomosis of the uterine artery with the uterine branch of the ovarian artery [15,16,17]
We argue that such an anatomical structure, including opposing flow within a single arterial loop, results in a hemodynamic enigma, in which the central fetuses receive little or even zero perfusion
Summary
Pregnancy in mammals requires coordinated adaptation of the systemic maternal cardiovascular system and remodeling of the entire uterine circulation, to assure adequate oxygenation and nutrient delivery to the developing embryo/fetus [1,2,3]. The direction of blood flow in the single uterine arterial loop was described as being dominated by the uterine branch of the ovarian artery in the cranial portion of each horn, and by the distal part of the uterine artery on the caudal end Such counter flow within this single loop was postulated to result in a significant drop in pressure and flow velocity to the central embryos/fetuses in each uterine horn [16,17]. We argue that such an anatomical structure, including opposing flow within a single arterial loop, results in a hemodynamic enigma, in which the central fetuses receive little or even zero perfusion This appears to be an unfavorable structure for maintaining stable and robust distribution of perfusion between placentas in a large litter, as the middle fetuses may not survive the course pregnancy. Opposing flow within a single arterial loop is unreasonable in terms of the hemodynamics of blood flow
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