Published online before print February 19, 2007, doi: 10.1161/01.HYP.0000259936.54206.7e
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(Hypertension. 2007;49:775.)
© 2007 American Heart Association, Inc.
Editorial Commentaries |
Prenatal Influences and Endothelial Dysfunction
A Link Between Reduced Placental Perfusion and Preeclampsia
From the Department of Physiology, University of Mississippi Medical Center, Jackson.
Correspondence to Barbara T. Alexander, Department of Physiology, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail balexander{at}physiology.umsmed.edu
Hypertension during pregnancy when associated with new-onset proteinuria is termed "preeclampsia."1,2 Preeclampsia is thought to initiate with improper remodeling of the uterine spiral arteries leading to reduced placental/fetal perfusion and subsequent extensive dysfunction of the maternal vascular endothelium.1,2 Reduced placental perfusion, however, may not always result in preeclampsia.1 Additionally, reduced placental perfusion may not necessarily reflect an imbalance between nutrient delivery and the metabolic needs of the fetus. Nonetheless, based on the fact that low placental perfusion is not always associated with preeclampsia, Roberts and Gammill1 proposed that the maternal response to reduced placental perfusion requires interaction with pre-existing maternal factors. Maternal factors that may contribute to increased maternal susceptibility to reduced placental perfusion and development of preeclampsia or hypertensive disorders of pregnancy include genetic, behavioral, and environmental factors.1
Numerous studies indicate that a genetic component may contribute to increased risk for preeclampsia and hypertensive disorders of pregnancy.1,3,4 Women and men born to a woman with preeclampsia are at greater risk for developing, or fathering, a preeclamptic pregnancy, suggesting transmission of a fetal gene for increased susceptibility to preeclampsia.3,4 However, this susceptibility is greater in women than in men, suggesting passage of maternal susceptibility genes from mother to daughter in addition to fetal susceptibility genes.3,4
Behavioral and environmental risk factors for preeclampsia include obesity, hypertension, and type 2 diabetes1,5; all of these are risk factors for development of cardiovascular disease and are characterized by endothelial dysfunction.6 Cardiovascular disease, including hypertension, is thought to result from genetic and environmental factor interactions. Recent epidemiological studies report an inverse relationship between weight at birth and blood pressure, suggesting that influences in the prenatal environment that slow fetal growth may also modulate postnatal patterns of gene expression leading to increased risk for cardiovascular disease in later life,7 an observation strongly supported by animal studies.8–10 Reduced perfusion to the placenta and fetus is one insult that can permanently alter or "program" both the structure and physiology of the fetus.7–10 Postnatal stress may exacerbate the prenatal effects of programming and contribute to development of obesity, hypertension, and type 2 diabetes.7,8,10
Although reduced placental perfusion may result in intrauterine growth restriction, the maternal response does not always result in preeclampsia.1 Thus, intrauterine growth restriction in a normotensive pregnancy suggests that the maternal response to reduced placental perfusion is absent, indicating a lack of susceptibility genes, either fetal and/or maternal, and a lack of maternal behavioral or environmental risk factors. In this issue of Hypertension, Rasmussen and Irgens11 report that women born small after a normotensive pregnancy are more likely to develop preeclampsia and hypertensive disorders of pregnancy. Moreover, Rasmussen and Irgens11 report that fathers born small are not associated with their partner’s risk for development of preeclampsia and hypertensive disorders of pregnancy. Therefore, although a genetic component cannot be ruled out, it is unlikely that susceptibility genes, either of fetal or maternal origin, contribute to the increased risk for women born small from a normotensive pregnancy to develop preeclampsia or hypertension in their own pregnancies.
Endothelial dysfunction is observed in both children and adults born small7; endothelial dysfunction is also observed in animal models of reduced uterine perfusion and fetal malnutrition.7,8,10 Germain et al,12 report that maternal endothelial dysfunction may contribute to placentation-related defects, such as pre-eclampsia. Therefore, pre-existing maternal endothelial dysfunction may serve as a link between reduced placental perfusion and the maternal response.1,12 Because endothelial dysfunction is a reported consequence of being born small, it may serve as the link between reduced placental perfusion and the increased risk for development of preeclampsia and hypertensive disorders of pregnancy in women born small. Therefore, adverse consequences of reduced placental perfusion may lead to prenatal induced alterations in endothelial function in women born small, enhancing not only their risk for development of cardiovascular disease in later life but also their risk for development of preeclampsia and hypertensive disorders of pregnancy. Confounding behavioral and environmental factors derived from health consequences of obesity, type 2 diabetes, and cardiovascular and renal disease are all risk factors for individuals born small.7 The presence of these confounding factors may exacerbate maternal susceptibility to reduced placental perfusion and development of pregnancy-induced hypertension and preeclampsia in women born small. However, within the study by Rasmussen and Irgens,11 inclusion of these conditions provided negligible effects on the association of born small and pregnancy-induced hypertension, suggesting that endothelial dysfunction can serve as a major component of maternal susceptibility and hypertensive disorders during pregnancy (Figure).
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Adverse prenatal influences can have long-term effects contributing to cardiovascular disease. There is now evidence to suggest that, in women, prenatal insults may also contribute to their risk for development of hypertensive disorders of pregnancy. Thus, prenatal origins of endothelial dysfunction may initiate susceptibility and enhance the maternal response to improper vascular remodeling, resulting in pregnancy-induced hypertension.
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Acknowledgments |
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Sources of Funding
B.T.A. is supported by grants from the National Institutes of Health (HL074927 and HL51971).
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
This paper was sent to Norman M. Kaplan, consulting editor, for review by expert referees, editorial decision, and final disposition.
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References |
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 Top References |
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- Roberts JM, Gammill HS. Preeclampsia: recent insights. Hypertension. 2005; 46: 1243–1249.
[Abstract/Free Full Text] - Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction. Hypertension. 2001; 38: 718–722.
[Abstract/Free Full Text] - Nilsson E, Salonen R, Cnattingius S, Lichtenstein Pl. The importance of genetic and environmental effects for pre-eclampsia and gestational hypertension: a family study. Br J Obstet Gynaecol. 2004; 111: 200–206.
- Skjærven R, Vatten LJ, Wilcox AJ, Rønning T, Irgens LM, Lie RT. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ. 2005; 331: 877–882.
[Abstract/Free Full Text] - Barden A. Pre-eclampsia: contribution of maternal constitutional factors and the consequences for cardiovascular health. Clin Exp Pharmacol Physiol. 2006; 33: 826–830.[CrossRef][Medline] [Order article via Infotrieve]
- Kaplan NM, Opie LH. Controversies in hypertension. Lancet. 2006; 367: 168–176.[CrossRef][Medline] [Order article via Infotrieve]
- Barker DJP. Mothers, Babies, and Health in Later Life. Edinburgh, United Kingdom: Churchill Livingstone; 1998.
- Louey S, Thornburg KL. The prenatal environment and later cardiovascular disease. Early Human Dev. 2005; 81: 745–751.[CrossRef][Medline] [Order article via Infotrieve]
- Alexander BT. Placental insufficiency leads to development of hypertension in growth restricted offspring. Hypertension. 2003; 41: 457–462.
[Abstract/Free Full Text] - Alexander BT. Fetal programming of hypertension Am J Physiol. 2006; 290: R1–R10.[CrossRef]
- Rasmussen S, Irgens LM. Pregnancy-induced hypertension in women who were born small. Hypertension. 2007; 49: 806–812.
[Abstract/Free Full Text] - Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, Price K, Karumanchi SA, Valdes G. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension. 2007; 49: 90–95.
[Abstract/Free Full Text]
Related Article:
- Pregnancy-Induced Hypertension in Women Who Were Born Small
- Svein Rasmussen and Lorentz M. Irgens
Hypertension 2007 49: 806-812.[Abstract] [Full Text] [PDF]
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