Pregnancy-associated homeostasis and dysregulation: lessons from genetically modified animal models.

Physiological alterations occur in many organ systems during pregnancy. These changes are necessary for the adaptation to pregnancy-specific physiological processes in mother and fetus, and the placenta plays a critical role in the maintenance of homeostasis in pregnancy. Dysregulation of these functional feto-maternal interactions leads to severe complications. There have been many attempts to create animal models that mimic the hypertensive disorders of pregnancy, especially pre-eclampsia. In this review, we summarize the physiology of pregnancy and placental function, and discuss the placental gene expression in normal pregnancy. In addition, we assess a number of established animal models focusing on a specific pathogenic mechanism of pre-eclampsia, including genetically modified mouse models involving the renin-angiotensin system. Validation of these animal models would contribute significantly to understanding the basic principles of pregnancy-associated homeostasis and the pathogenesis of pre-eclampsia.

Impaired placental neovascularization in mice with pregnancy-associated hypertension.

Preeclampsia is a serious disorder that may result in severe morbidity and mortality for mother and fetus, and it is thought that the placental dysfunction is important in the pathogenesis of preeclampsia. As the model of preeclampsia, we previously generated a transgenic mouse model that developed pregnancy-associated hypertension (PAH) by mating females expressing human angiotensinogen with males expressing human renin. In PAH mice, maternal blood pressure started to rise from days 12 to 13 of gestation (E12-13) to term (E19-20), which is accompanied by the fetal intrauterine growth retardation and systemic maternal disorders including proteinuria and convulsion. To understand the pathology of the complications in PAH mice that overlap with those in human preeclampsia, we analyzed the PAH placenta sequentially from the onset of hypertension to the term of delivery. In PAH placenta, histological analysis revealed that the microvessel densities of fetal vasculature at term were significantly lower than those of normal placenta, and the majority of terminal vessels of PAH placenta were lacking for pericytes and basement membrane. The interaction between fetal vasculature and maternal blood canal at labyrinth of PAH placenta was morphologically distorted, and the expression patterns of key molecules in neovascularization of PAH placenta were distinct from those of normal placenta during pregnancy. In addition, maternal plasma level of soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1) was significantly increased in PAH at E19. Furthermore, in uteroplacental site, in situ proteolytic activity of PAH mice was suppressed from E16 to term compared to that of normal pregnancy, and the expression of matrix metalloproteinase-2 mRNA was strikingly downregulated at E16 in PAH mice. Collective data suggest that the impairments of fetoplacental neovascularization and uteroplacental remodeling contribute to the development of complications in PAH.

Angiotensin type 1 receptor blockade prevents cardiac remodeling in mice with pregnancy-associated hypertension.

Pregnancy-induced hypertension (PIH) is a life-threatening disorder for both mother and fetus; cardiac dysfunction is the major complication and can result in further deterioration. Recently, it has been recognized that aberrant activation of angiotensin type 1 receptor (AT1) signaling contributes to the pathogenesis of PIH, but the details of the relationship between cardiac injury and enhanced AT1 signaling in PIH are still unclear. We previously generated a transgenic mouse model of pregnancy-associated hypertension (PAH) via overproduction of angiotensin II, an endogenous ligand of AT1, in the maternal circulation during late pregnancy. In the present study, we administered olmesartan, an AT1 blocker, to suppress redundant AT1 signaling in PAH mice and evaluated the efficacy of this treatment in cardiac remodeling. Olmesartan treatment significantly lowered the blood pressure of PAH mice, and hypertrophy as well as increased plasma levels of cardiac injury markers were also markedly reduced. Histological analyses revealed that morphological abnormalities and fibrosis in the hearts of PAH mice recovered to the levels of normal pregnant wild-type mice after the administration of olmesartan. Moreover, in fibrotic regions of PAH hearts, olmesartan treatment significantly decreased the extent of cardiac injury and apoptosis. These results indicate that the activation of AT1 signaling pathways during maternal hypertension plays a critical role in cardiac remodeling in PAH mice, and suggest that treatment with an AT1 blocker could effectively ameliorate cardiac dysfunction during pregnancy with hypertension in vivo.