20 Defective placental bed vascular remodeling precedes manifestations of superimposed preeclampsia in stroke-prone spontaneously hypertensive rats

Abstract

Introduction Pregnant women suffering from chronic hypertension are at increased risk of developing superimposed preeclampsia (SPE), often associated with poor fetal and maternal outcomes. Most animal models available to date reproduce ‘de novo' PE-like features through different experimental approaches, but the development of a SPE syndrome in pregnant animals with pre-existing arterial hypertension has been greatly overlooked in basic research pertaining hypertensive pregnancies. Objectives To characterize timed pregnancies in the Stroke Prone Spontaneously Hypertensive Rat (SHRSP) strain, a well-known model for essential hypertension, focusing on the development of clinical, fetal and placental manifestations of SPE. Methods SHRSP and Wistar Kyoto (WKY) females (10–12weeks old, N =5animals/day analyzed) were mated to congenic males and checked daily for vaginal plugs, denoted as gestation day (GD) 1. Blood pressure (BP) was determined by the tail-cuff method pre-mating and on the morning of GD1, 7, 9, 13, 17 and 19. On the selected dates, females were housed in metabolic cages for collection of 24h urine samples. Following collection of blood samples, animals were euthanized and implantation sites isolated for morphological analyzes. Fetal and placental weights were recorded on GD 18 and GD20. Results Compared to WKY, the SHRSP exhibited a significant elevation of baseline hypertension towards the last third of pregnancy (i.e, from GD13 to GD20) together with increased protein excretion, considered diagnostic hallmarks for SPE. Renal compromise was also evident as a progressive decrease of urinary output and histopathological changes in the glomerular and tubulointerstitial compartments of SHRSP kidneys. The SHRSP offspring were growth restricted and morphometrical analyzes showed underlying abnormal placentation, including signs of placental insufficiency such as decreased fetal to placental weight ratio and hypertrophy of the labyrinth layer linked to defective vascularization. Notably, our analysis also showed that the onset of the maternal syndrome was preceded by incomplete remodeling of the placental bed spiral arteries, which showed luminal narrowing and decreased densities of perivascular uterine NK cells at GD14 followed by defective infiltration of endovascular trophoblasts at GD18. Conclusion Our data confirms the characterization of pregnant SHRSP as a model reproducing clinical diagnostic traits and the underlying placental pathology observed in preeclampsia superimposed on chronic hypertension. This novel model provides an attractive system for interventional studies and dissection of the multifactorial origins of hypertensive disorders of pregnancy.