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Review
. 2012 Jul;123(2):53-72.
doi: 10.1042/CS20110627.

Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies

Esther F Davis  1 , Laura Newton, Adam J Lewandowski, Merzaka Lazdam, Brenda A Kelly, Theodosios Kyriakou, Paul Leeson
Affiliations
Review

Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies

Esther F Davis et al. Clin Sci (Lond). 2012 Jul.

Abstract

Pre-eclampsia is increasingly recognized as more than an isolated disease of pregnancy. Women who have had a pregnancy complicated by pre-eclampsia have a 4-fold increased risk of later cardiovascular disease. Intriguingly, the offspring of affected pregnancies also have an increased risk of higher blood pressure and almost double the risk of stroke in later life. Experimental approaches to identify the key features of pre-eclampsia responsible for this programming of offspring cardiovascular health, or the key biological pathways modified in the offspring, have the potential to highlight novel targets for early primary prevention strategies. As pre-eclampsia occurs in 2-5% of all pregnancies, the findings are relevant to the current healthcare of up to 3 million people in the U.K. and 15 million people in the U.S.A. In the present paper, we review the current literature that concerns potential mechanisms for adverse cardiovascular programming in offspring exposed to pre-eclampsia, considering two major areas of investigation: first, experimental models that mimic features of the in utero environment characteristic of pre-eclampsia, and secondly, how, in humans, offspring cardiovascular phenotype is altered after exposure to pre-eclampsia. We compare and contrast the findings from these two bodies of work to develop insights into the likely key pathways of relevance. The present review and analysis highlights the pivotal role of long-term changes in vascular function and identifies areas of growing interest, specifically, response to hypoxia, immune modification, epigenetics and the anti-angiogenic in utero milieu.

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Figures

Figure 1
Figure 1. Potential mechanism of cardiovascular programming in the offspring following a pre-eclamptic pregnancy
Summary of the potential and demonstrated mechanisms by which in utero exposure to pre-eclampsia may lead to altered cardiovascular physiology and risk in the offspring in later life.
Figure 2
Figure 2. Timing of the reduction in uterine artery perfusion and offspring BP
Summary of the results of studies (reference number given) considering the effect of RUPP at different points of gestation on offspring BP. Continuous lines indicate that studies have demonstrated an increase in BP in RUPP animals compared with controls at this time point, whereas broken lines indicate no difference in BP compared with controls. The colour of the lines indicates the timing of the in utero insult; the red line showing the result of studies in which uterine artery perfusion was reduced at day (D) 14, the blue line at day 18 and the green line at day 19 of gestation. This suggest that the timing of the insult may be critical in determining the effect on offspring BP. Studies of mid-gestation (14 days of gestation) reduction in uterine artery flow have demonstrated relatively consistent increases in BP from early life (4 weeks of age). Interventions later in gestation (days 18 and 19 of gestation) have not indicated consistent increases in early life, although some studies have indicated later development of hypertension which may be linked to dietary factors.
Figure 3
Figure 3. Cardiovascular changes associated with in utero exposure to hypoxia
The major findings from studies (reference number given) considering the effects of pre-natal chronic hypoxia at different points of gestation on offspring cardiovascular physiology are outlined. The colour of the lines indicates the timing of commencement of in utero hypoxia; The dark blue line indicates hypoxia for the entire period of gestation, the green line from day 5, the red line from day 6, the purple line from day 7, the orange line from day 15, and the pale blue line from day 18 of gestation. The percentage of oxygen used in each study is indicated above the lines. Studies have been divided into those where hypoxia was commenced in early pregnancy (before day 10 in rat models or from conception in other animals) and those where hypoxia was commenced later in pregnancy. Studies later in pregnancy have demonstrated vascular, cardiac and metabolic alterations in the offspring. Fewer studies have considered the effects of early-onset hypoxia, but these have demonstrated similar findings in terms of the vascular phenotype.
Figure 4
Figure 4. Effect of maternal systemic endothelial dysfunction during pregnancy on offspring BP
Experiments in eNOS-knockout mice have demonstrated the importance of the development in an environment of maternal systemic endothelial dysfunction. eNOS-knockout heterozygotes born to knockout mothers have shown some evidence of increased BP and BP variability compared with heterozygotes gestated in an environment with normal endothelial function. Second-generation offspring also show alterations in BP. Maternal systemic endothelial dysfunction during pregnancy is characteristic of the human syndrome of pre-eclampsia and these models highlight the potential importance of this in utero insult on later offspring vascular function [82].
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