Reduced Uterine Perfusion Pressure (RUPP) Model of Preeclampsia in Mice

Abstract

Preeclampsia (PE) is a pregnancy-induced hypertension with proteinuria that typically develops after 20 weeks of gestation. A reduction in uterine blood flow causes placental ischemia and placental release of anti-angiogenic factors such as sFlt-1 followed by PE. Although the reduced uterine perfusion pressure (RUPP) model is widely used in rats, investigating the role of genes on PE using genetically engineered animals has been problematic because it has been difficult to make a useful RUPP model in mice. To establish a RUPP model of PE in mice, we bilaterally ligated ovarian vessels distal to ovarian branches, uterine vessels, or both in ICR-strain mice at 14.5 days post coitum (dpc). Consequently, these mice had elevated BP, increased urinary albumin excretion, severe endotheliosis, and mesangial expansion. They also had an increased incidence of miscarriage and premature delivery. Embryonic weight at 18.5 dpc was significantly lower than that in sham mice. The closer to the ligation site the embryos were, the higher the resorption rate and the lower the embryonic weight. The phenotype was more severe in the order of ligation at the ovarian vessels < uterine vessels < both. Unlike the RUPP models described in the literature, this model did not constrict the abdominal aorta, which allowed BP to be measured with a tail cuff. This novel RUPP model in mice should be useful for investigating the pathogenesis of PE in genetically engineered mice and for evaluating new therapies for PE.

The Complement System and Preeclampsia

“…A mouse model of placental ischemia-induced hypertension has been recently described [96, 97]. Both mouse and rat have a hemochorial placenta resembling humans.…”

Animal models of preeclampsia: an examination of usefulness and limitations based on the metabolic domino theory

“…Therefore, as shown in Figure 3, the ideal animal model of preeclampsia is one in which development of the condition begins with immunogenic maladaptation, followed by the fall of multiple dominoes with progressing pathology. Even with RUPP models, which are widely used and considered useful for preeclampsia research, 26,27) the pathology of preeclampsia is not fully replicated, in which multiple dominoes fall, even in Stage 1, despite involving the fall of multiple dominoes in Stage 2.…”

“…As described above, if an animal model is to be used to study preeclampsia, it must be selected based on sufficient consideration of its advantages and disadvantages in relation to study objectives. For example, if the roles of sFlt-1 in preeclampsia pathogenesis are to be investigated, it is reasonable to use RUPP models, 27) or mice that overexpress sFlt-1, 28) as these models can be used for unified investigation of the effects of increased sFlt-1 on the pathology of preeclampsia. However, it remains unclear as to whether these models are appropriate for investigating the usefulness of drugs as therapeutic agents for preeclampsia.…”

Efectos de la Aspirina en Fetos de Rata con Reducción de la Presión de la Perfusión Uterina

“…Esta se determina por el aumento de la presión arterial en valores sobre 140 mmHg de presión sistólica y sobre 90 mmHg de presión diastólica, asociada a proteinuria que se desarrolla generalmente desde las 20 semanas de gestación (Ministerio de Salud, 2015). Sin embargo, también se puede asociar a otra sintomatología como insuficiencia renal o daño hepático (Fushima et al, 2016). Su patogenia está asociada a alteraciones en la placentación, con un remodelamiento vascular incompleto a nivel de las arterias espiraladas, que produce una disminución del flujo úteroplacentario, generando un estrés oxidativo que favorece la liberación de citoquinas proinflamatorias y la activación del endotelio donde disminuye la producción de prostaglandinas y óxido nítrico, y aumenta la producción de endotelina, dando como resultado una reducción del flujo placentario y un ambiente hipóxico patológico para el feto (Henderson et al, 2017).…”