Abstract
Intrauterine growth restriction (IUGR) is a risk factor for cardiovascular disease in later life. Early structural and functional changes in the cardiovascular system after IUGR may contribute to its pathogenesis. We tested the hypothesis that IUGR leads to primary myocardial and vascular alterations before the onset of hypertension. A rat IUGR model of maternal protein restriction during gestation was used. Dams were fed low protein (LP; casein 8.4%) or isocaloric normal protein diet (NP; casein 17.2%). The offspring was reduced to six males per litter. Immunohistochemical and real-time PCR analyses were performed in myocardial and vascular tissue of neonates and animals at day 70 of life. In the aortas of newborn IUGR rats expression of connective tissue growth factor (CTGF) was induced 3.2-fold. At day 70 of life, the expression of collagen I was increased 5.6-fold in aortas of IUGR rats. In the hearts of neonate IUGR rats, cell proliferation was more prominent compared to controls. At day 70 the expression of osteopontin was induced 7.2-fold. A 3- to 7-fold increase in the expression of the profibrotic cytokines TGF-β and CTGF as well as of microfibrillar matrix molecules was observed. The myocardial expression and deposition of collagens was more prominent in IUGR animals compared to controls at day 70. In the low-protein diet model, IUGR leads to changes in the expression patterns of profibrotic genes and discrete structural abnormalities of vessels and hearts in adolescence, but, with the exception of CTGF, not as early as at the time of birth. Invasive and non-invasive blood pressure measurements confirmed that IUGR rats were normotensive at the time point investigated and that the changes observed occurred independently of an increased blood pressure. Hence, altered matrix composition of the vascular wall and the myocardium may predispose IUGR animals to cardiovascular disease later in life.
Highlights
Cardiovascular events like stroke or myocardial infarction are among the leading factors of morbidity and mortality in the western worId
Low protein diet in the pregnant dams led to a significant reduction of birth weights of their offspring
Systolic blood pressure was comparable in the low protein (LP) and normal protein diet (NP) group as assessed by tail cuff blood pressure measurements performed in 70 days old rats (134.567.03 mmHg in NP versus 127.365.03 mmHg in LP, n.s.)
Summary
Cardiovascular events like stroke or myocardial infarction are among the leading factors of morbidity and mortality in the western worId. Studying the aetiopathogenetic interrelation between the fetal and neonatal problem of IUGR and cardiovascular diseases at adulthood, Barker and colleagues created the term of ‘‘fetal programming’’ They postulated that fetal adaptation to an adverse intrauterine environment modifies cellular differentiation and tissue structure permanently and impairs cardiovascular structure, function and integrity [6,7]. In this context it could be shown in animal studies, that IUGR associated intrauterine hypoxia leads to an altered myocardial vasculature which causes a reduced cardial performance and the morphological phenotype of dilated cardiomyopathy [8,9]. Several studies in humans confirmed that a number of early changes in vessel walls are associated with IUGR [12,13,14]
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