Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress.

Dino A Giussani,Avnesh S Thakor,F B Peter Wooding,Jeremy A Hansell,Emilio A Herrera,Christine M Cross,Carlos E Blanco,Youguo Niu,Andrew D Kane,Katy A Horder,Emily J Camm,Hans G Richter,E Zachary Blake,Rachel Gottschalk,Jose A L Calbet

doi:10.1371/journal.pone.0031017

Abstract

Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O2) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.

Highlights

Cardiovascular disease is the greatest killer in the world today, imposing a substantial burden on every nation’s health and wealth [1]
Maternal treatment with vitamin C in hypoxic pregnancy restored the aortic wall thickness, aortic wall nitrotyrosine staining and the cardiac expression of HSP70 to values measured in normoxic pregnancy (Fig. 1A–D)
Maternal treatment with vitamin C in normoxic pregnancy did not affect the morphology of the heart or aorta, or the levels of nitrotyrosine in the aortic wall or of HSP70 in the heart (Table 1; Fig. 1A–D)

Summary

Introduction

Cardiovascular disease is the greatest killer in the world today, imposing a substantial burden on every nation’s health and wealth [1]. The concept that environmental risk factors, such as smoking and obesity, interact with our genetic makeup to determine susceptibility to cardiovascular dysfunction is well accepted [2]. In pregnancy complicated with adverse intrauterine conditions, adaptations are enforced in the unborn child and placenta, which can alter the development of key organs and systems, such as the heart and circulation Whilst they are necessary to maintain viable pregnancy and sustain life before birth, these adaptations come at a cost, triggering many biological trade-offs for later life. Insults at critical stages of development may lead to permanent changes in tissue structure and function, a concept known as programming [5]. The concept creates an exciting window of opportunity to halt the development of cardiac and vascular dysfunction at its very origin, bringing preventive medicine back into the womb. The mechanisms underlying developmental programming remain elusive, precluding the identification of potential avenues for clinical therapy [6,7]

Methods

Results

Conclusion