Discovery of a Spontaneous Genetic Mouse Model of Preeclampsia

Abstract

Abstract-Preeclampsia remains a leading cause of maternal and fetal morbidity and mortality but has an unknown etiology. Women with elevated baseline blood pressure have an increased risk of this disorder. We hypothesized that BPH/5 mice, an inbred mouse strain with mildly elevated blood pressure, would develop a pregnancy-induced hypertensive syndrome. Nonpregnant female BPH/5 and C57BL/6 mice underwent thoracic aortic implantation of telemeters. After 7 days of recovery and 5 days of baseline mean arterial blood pressure (MAP) recording, strain-matched timed matings were carried out. MAP was recorded continuously during pregnancy and for 1 week after birth. In separate mice in metabolic cages, urinary protein was tracked, followed by renal histological analysis. Before pregnancy, the BPH/5 strain had elevated baseline MAP compared with the C57BL/6 strain, but both strains had similar total urinary protein levels and renal histology. MAP remained stable in both groups during the first 2 weeks of pregnancy. However, at the start of the last trimester, MAP began to rise further in the BPH/5 mice; it rose to peak levels just before delivery and returned to prepregnancy levels by 2 days after delivery. This was accompanied by late-gestational proteinuria and progressive glomerulosclerosis. No changes were observed in the C57BL/6 group except for a small decrease in MAP at mid gestation. The BPH/5 group delivered significantly smaller litters despite normal numbers of fetuses early in gestation, and longitudinal ultrasound studies documented fetal demise before the onset of hypertension and renal disease. This is the first report of an animal model that spontaneously develops a syndrome that bears close resemblance to preeclampsia, and it should have an impact on our understanding of the pathophysiology of this disorder. Key Words: hypertension, gestational Ⅲ blood pressure Ⅲ pregnancy Ⅲ proteinuria Ⅲ preeclampsia P reeclampsia, the most prevalent hypertensive disorder of pregnancy, is defined by the development of hypertension and proteinuria after the 20th week of pregnancy. It is thought to have an impact on 6% to 10% of pregnancies and is the leading cause of maternal mortality in Western countries. 1 A distinguishing feature of the disorder is its complete resolution after delivery of the fetus and placenta, the only known effective means to avoid cataclysmic progression to overt eclampsia. The necessity for urgent preterm delivery, along with progressive intrauterine growth restriction, implicates preeclampsia as a leading cause of perinatal morbidity and mortality. 2 The preeclampsia/eclampsia syndrome was described by ancient civilizations. Despite considerable research effort to date, we still understand very little about its etiology and pathophysiology, which are complex and multifactorial. 3 Clinical research is difficult because of the logistics of testing hypotheses related to pathogenesis or treatment in an urgent high-risk setting. Development of an animal model that fully recapitulates this complex ...

Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

“…The disease spontaneously develops in no quadruped, although a recently described genetic mouse model by Davisson et al seems to be an exception. 11 The combination of upright posture and uteroplacental ischemia may be necessary for manifestation of the full syndrome. 12 Chronic nitric oxide synthase inhibition in rats produces a pattern of change that resembles the symptoms of preeclampsia, and the preeclamptic-like response of rats with adriamycin nephropathy and hyperinsulinemia is associated with endothelial dysfunction.…”

Introducing a mouse model for pre‐eclampsia: adoptive transfer of activated Th1 cells leads to pre‐eclampsia‐like symptoms exclusively in pregnant mice

“…Over the past decade, various mammalian models to investigate the pathophysiology of PE have been suggested; however, their validity was hampered by the fact that in most of them, the non-pregnant control animals also developed PE-like symptoms [14][15][16][17][18][19]. Here, we introduce a new model in which activated Th1 cells are transferred into pregnant or non-pregnant recipients, which leads to PE-like symptoms exclusively in pregnant mice.…”

“…To date, some PE animal models have been proposed in the rabbit, rat and mouse [14][15][16][17][18][19]. The experimental design of such models was primarily based on mechanisms involved in the regulation of vasoconstriction/ vasodilation, i.e.…”

“…However, data delineating the pregnancy-specificity of these symptoms were not provided. Lastly, another approach was to employ genetically hypertensive mouse strains [19].…”

Translational Analysis of Mouse and Human Placental Protein and mRNA Reveals Distinct Molecular Pathologies in Human Preeclampsia

“…Further support for this hypothesis comes from the variety of mechanisms resulting in PE-like symptoms in mouse models. PE mouse models have been generated genetically from spontaneous hypertensive mice (5), by excessive angiotensin pathway activation (6), and by mutations affecting trophoblast cell cycle regulation (7). Interestingly, the anti-angiogenic factor, sFLT1, is present in elevated levels in the maternal circulation in most human PE pregnancies, but not all (8), and in some mouse models of PE (e.g.…”