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.