Intrauterine growth restriction promotes vascular remodelling following carotid artery ligation in rats

Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
Clinical Science (Impact Factor: 5.6). 04/2012; 123(7):437-44. DOI: 10.1042/CS20110637
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    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.
    Preview · Article · Jul 2013 · Clinical Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: Integrins play an important role in vascular biology. The α8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of α8 integrin to atherosclerosis and vascular remodelling. We hypothesized that α8 integrin expression is reduced in atherosclerotic lesions and that its underexpression leads to a more severe course of atherosclerosis. α8 integrin was detected by immunohistochemistry and qPCR. α8 integrin-deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross sections. Second, after crossing into ApoE-deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed. α8 integrin was detected in the media of human and murine vascular tissue and was downregulated in arteries with advanced atherosclerotic lesions. In α8 integrin-deficient mice (α8−/−) as well as α8+/− and α8+/+ littermates carotid artery ligation increased media-to-lumen ratios in all genotypes, with higher values in ligated α8−/− and α8+/− compared to ligated α8+/+ animals. Carotid artery ligation increased smooth muscle cell number in the media of α8+/+ mice, and more prominently of α8−/− or α8+/− mice. On an ApoE−/− background, α8+/− and α8−/− mice developed more atherosclerotic plaques than α8+/+ mice. α8 integrin expression was reduced in α8+/− animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in α8−/− mice only. Thus, underexpression of α8 integrin aggravates vascular lesions, while a complete loss of α8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin α8β1 has a protective role in arterial remodelling and atherosclerosis.
    No preview · Article · Dec 2014 · The Journal of Pathology