KL 10 Animal models for gestational hypertension

The prevalence of cardiovascular diseases and particularly of hypertension is increasing worldwide. Consequently, the number of women with hypertension in pregnancy is also increasing. Several rodent models of hypertension have been characterised in depth but only few models exhibit the complex cardiovascular phenotype that is typically seen in human hypertension. The stroke-prone spontaneously hypertensive rat (SHRSP) is characterised by hypertension, organ damage including left ventricular hypertrophy and stroke, metabolic disorders and a more severe phenotype in male compared to female rats. Whilst the majority of research in rodent pregnancy focusses on models of pre-eclampsia we are particularly interested in the adaptation to pregnancy in pre-existing hypertension. As such, the SHRSP is an ideal model for our studies. We have recently described important features of pregnant SHRSP that will help to understand human hypertensive pregnancy. We have demonstrated impaired uterine artery remodelling and reduced uteroplacental blood flow compared to the normotensive Wistar Kyoto strain (WKY), paralleled by impaired uterine artery endothelial function. Vascular changes in the pregnant SHRSP are associated with a unique inflammatory profile resulting in increased placental and systemic TNF-alpha levels. The TNF-alpha receptor antagonist etanercept improves uterine artery function and reduces blood pressure in the pregnant SHRSP. Natural Killer (NK) cells appear to contribute to placental TNF-alpha production in the SHRSP and etanercept causes a change in cytotoxicity of these NK cells. We are currently exploring how an even more severe hypertensive phenotype in the SHRSP affects pregnancy outcome and if we can observe features of superimposed pre-eclampsia in this model. To this end, we expose pregnant SHRSP to high salt diet or angiotensin II. In parallel to hypothesis driven experiments we perform unbiased screens in the pregnant and non-pregnant SHRSP, focussing on transcriptomic, peptidomic and proteomic approaches. In summary, the SHRSP is an excellent model to study the effects of chronic hypertension on the physiological changes associated with pregnancy.