Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative physiology

Abstract

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of pre-eclampsia have yet to be fully elucidated. However, it is evident that this is a complex disorder involving multiple organ systems, and by using integrative approaches, enormous progress has been made towards understanding the pathophysiology of pre-eclampsia. Growing evidence supports the concept that the placenta plays a central role in the pathogenesis of pre-eclampsia and that reduced uteroplacental perfusion, which develops as a result of abnormal cytotrophoblast invasion of spiral arterioles, triggers the cascade of events leading to the maternal disorder. Placental ischaemia leads to release of soluble placental factors, many of which are classified as anti-angiogenic or pro-inflammatory. Once these ischaemic placental factors reach the maternal circulation, they cause widespread activation and dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin-1 and superoxide, increased vascular sensitivity to angiotensin II and decreased formation of vasodilators such as nitric oxide. This review highlights these links between placental ischaemia, maternal endothelial activation and renal dysfunction in the pathogenesis of hypertension in pre-eclampsia.

Figure 1

Vascular corrosion casting was used to examine maternal blood spaces of the placenta from mice at embryonic (E) days 10.5 and 14.5. The trophoblast cell-lined vascular canals supplying blood to the placenta were smaller from Notch2 knockout (KO) compared to wild type (WT) rats at both embryonic days. These data indicate that Notch2 is important for proper remodeling of the placental vasculature. Figure adapted from Hunkapiller et al., 2011.

Figure 2

Systolic blood pressure in wild type (WT) female rats mated with transgenic male mice overexpressing the STOX13, one of the transgenic lines generated to overexpress the transcription factor STOX1, or male WT mice. This mating strategy resulted in pregnant female having placentas overexpressing or having normal expression of STOX1, respectively. Female mice with overexpression of placental STOX1 developed a progressive hypertensive phenotype that subsided after parturition. Figure adapted from Doridot et al., 2013.

Figure 3

Renal cortical mRNA expression of preproET-1 in normal pregnant (NP) rats infused with sFlt-1 from embryonic days 14-19 (A) and mean arterial blood pressure (MAP) in NP rats infused with sFlt-1 co-treated with or without the ET_A receptor antagonistic ABT-627 (B). sFlt-1-induced hypertension was linked to greater renal expression of ET-1 and the blood pressure response was dependent ET-1. Figure adapted from Murphy et al., 2010.

Figure 4

Hypothetical scheme depicting how abnormal cytotrophoblast invasion and subsequent reductions in spiral artery remodeling results in endothelial dysfunction and hypertension in preeclampsia.