Abstract
BackgroundIntrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.MethodsChick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.Principal FindingsGrowth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.Conclusions/SignificanceOur data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.
Highlights
Epidemiological studies have shown that intrauterine stress, reflected by intrauterine growth restriction and low birth weight, increases the risk of developing cardiovascular diseases later in life [1,2,3,4,5]
We demonstrated that embryonic hypoxia results in cardiac disease at both late embryonic stages and adulthood in a chick model
We identified a putative role for elevated cardiac VEGF165 levels in the etiology of hypoxia-initiated cardiac disease
Summary
Epidemiological studies have shown that intrauterine stress, reflected by intrauterine growth restriction and low birth weight, increases the risk of developing cardiovascular diseases later in life [1,2,3,4,5]. A common cause of fetal growth restriction in clinical practice is intrauterine hypoxia due to uteroplacental insufficiency [6,7]. The aim of the present study was to further characterize the effects of embryonic hypoxia on cardiac structure and function. Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos
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