Intrauterine growth restriction promotes vascular remodelling following carotid artery ligation in rats.
ABSTRACT Epidemiological studies revealed an association between IUGR (intrauterine growth restriction) and an increased risk of developing CVDs (cardiovascular diseases), such as atherosclerosis or hypertension, in later life. Whether or not IUGR contributes to the development of atherosclerotic lesions, however, is unclear. We tested the hypothesis that IUGR aggravates experimentally induced vascular remodelling. IUGR was induced in rats by maternal protein restriction during pregnancy (8% protein diet). To detect possible differences in the development of vascular injury, a model of carotid artery ligation to induce vascular remodelling was applied in 8-week-old intrauterine-growth-restricted and control rat offspring. Histological and immunohistochemical analyses were performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. IUGR alone neither caused overt histological changes nor significant dedifferentiation of VSMCs (vascular smooth muscle cells). After carotid artery ligation, however, neointima formation, media thickness and media/lumen ratio were significantly increased in rats after IUGR compared with controls. Moreover, dedifferentiation of VSMCs and collagen deposition in the media were more prominent in ligated carotids from rats after IUGR compared with ligated carotids from control rats. We conclude that IUGR aggravates atherosclerotic vascular remodelling induced by a second injury later in life.
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ABSTRACT: The developmental origins of the metabolic syndrome have been established through the consistent observation that small-for-gestational age and large-for-gestational age fetuses have an increased risk for hypertension and related metabolic disorders later in life. These phenotypes have been reproduced in various species subjected to a range of intrauterine insults and ongoing research is directed towards understanding the underlying molecular mechanisms. Current evidence suggests that the creation of a pro-inflammatory and pro-oxidant intrauterine milieu is a common thread among prenatal factors that have an impact upon fetal size. Furthermore, studies demonstrate that a shift in fetal redox status consequent to environmental cues persists after birth and drives the progression of vascular dysfunction and hypertension in postnatal life. TLR (Toll-like receptor) signalling has emerged as a key link between inflammation and oxidative stress and a pathogenic contributor to hypertension, insulin resistance and obesity, in both human patients and animal models of disease. Thus TLR activation and dysregulation of its signalling components represent potential molecular underpinnings of programmed hypertension and related disorders in those subjected to suboptimal intrauterine conditions, yet their contributions to developmental programming remain unexplored. We propose that danger signals mobilized by the placenta or fetal tissues during complicated pregnancy activate the fetal innate immune system through TLRs and thereby potentiate the generation of ROS (reactive oxygen species) and orchestrate fetal adaptive responses, including changes in gene expression, which later translate to vascular dysfunction. Furthermore, we suggest that, after birth, continual activation of TLR signalling propagates vascular oxidative stress and thereby accelerates the advancement of hypertension and heart failure.Clinical Science 01/2013; 125(1):19-25. · 4.86 Impact Factor