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Early and late postnatal myocardial and vascular changes in a protein restriction rat model of intrauterine growth restriction.

Menendez-Castro C, Fahlbusch F, Cordasic N, Amann K, Münzel K, Plank C, Wachtveitl R, Rascher W, Hilgers KF, Hartner A - PLoS ONE (2011)

Bottom Line: The offspring was reduced to six males per litter.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany. carlos.menendez-castro@uk-erlangen.de

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.

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Examples of myocardial stainings for osteopontin.Representative photomicrographs of immunostainings for osteopontin (OPN) in myocardial tissue of neonatal control rats and neonatal rats with intrauterine growth restriction (neo); and in myocardial tissue of control rats and rats with intrauterine growth restriction at day 70 of life (d70). NP, control rats; LP, rats with intrauterine growth restriction. Arrow indicates positive immunoreactivity for OPN in the media of myocardial vessels in LP at day 70.
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pone-0020369-g003: Examples of myocardial stainings for osteopontin.Representative photomicrographs of immunostainings for osteopontin (OPN) in myocardial tissue of neonatal control rats and neonatal rats with intrauterine growth restriction (neo); and in myocardial tissue of control rats and rats with intrauterine growth restriction at day 70 of life (d70). NP, control rats; LP, rats with intrauterine growth restriction. Arrow indicates positive immunoreactivity for OPN in the media of myocardial vessels in LP at day 70.

Mentions: In order to study possible differences in the inflammatory response of LP and NP rats, we performed expression analyses of inflammation markers and studied macrophage infiltration in aortas and hearts of newborn rats and rats at day 70 of life. Macrophage infiltration into the aortas of newborn and 70 days old rats occurred very rarely and was comparable in LP and NP rats (table 3). In contrast, macrophage infiltration in the myocardium was reduced in the LP neonates (table 3) while at day 70 of life, myocardial macrophage infiltration was not different between NP and LP animals anymore (table 3). In the aortas of neonate rats and of rats at day 70 of life, the mRNA levels of the chemokines MCP-1 and osteopontin were below detection limits and therefore were not further evaluated. In the hearts of neonate LP rats, MCP-1 and osteopontin expression was not significantly different from NP animals (table 3). At day 70 of life, myocardial MCP-1 expression tended to be higher in LP than in NP rats. However, due to the large variability in LP rats, this increase did not reach statistical significance (p = 0.14; table 3). In contrast, the expression of osteopontin was significantly augmented in the hearts of 70 days old LP rats compared to NP rats (table 3). In order to localize the tissue compartment responsible for the increase in osteopontin expression, immunohistochemistry for osteopontin in the myocardium was performed. While in neonate heart tissue no differences in staining patterns between NP and LP rats were observed (figure 3), osteopontin immunohistochemistry in the hearts of rats at day 70 of life revealed a distinct staining of the media of myocardial vessels in LP animals which was not detected in NP animals (figure 3).


Early and late postnatal myocardial and vascular changes in a protein restriction rat model of intrauterine growth restriction.

Menendez-Castro C, Fahlbusch F, Cordasic N, Amann K, Münzel K, Plank C, Wachtveitl R, Rascher W, Hilgers KF, Hartner A - PLoS ONE (2011)

Examples of myocardial stainings for osteopontin.Representative photomicrographs of immunostainings for osteopontin (OPN) in myocardial tissue of neonatal control rats and neonatal rats with intrauterine growth restriction (neo); and in myocardial tissue of control rats and rats with intrauterine growth restriction at day 70 of life (d70). NP, control rats; LP, rats with intrauterine growth restriction. Arrow indicates positive immunoreactivity for OPN in the media of myocardial vessels in LP at day 70.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105022&req=5

pone-0020369-g003: Examples of myocardial stainings for osteopontin.Representative photomicrographs of immunostainings for osteopontin (OPN) in myocardial tissue of neonatal control rats and neonatal rats with intrauterine growth restriction (neo); and in myocardial tissue of control rats and rats with intrauterine growth restriction at day 70 of life (d70). NP, control rats; LP, rats with intrauterine growth restriction. Arrow indicates positive immunoreactivity for OPN in the media of myocardial vessels in LP at day 70.
Mentions: In order to study possible differences in the inflammatory response of LP and NP rats, we performed expression analyses of inflammation markers and studied macrophage infiltration in aortas and hearts of newborn rats and rats at day 70 of life. Macrophage infiltration into the aortas of newborn and 70 days old rats occurred very rarely and was comparable in LP and NP rats (table 3). In contrast, macrophage infiltration in the myocardium was reduced in the LP neonates (table 3) while at day 70 of life, myocardial macrophage infiltration was not different between NP and LP animals anymore (table 3). In the aortas of neonate rats and of rats at day 70 of life, the mRNA levels of the chemokines MCP-1 and osteopontin were below detection limits and therefore were not further evaluated. In the hearts of neonate LP rats, MCP-1 and osteopontin expression was not significantly different from NP animals (table 3). At day 70 of life, myocardial MCP-1 expression tended to be higher in LP than in NP rats. However, due to the large variability in LP rats, this increase did not reach statistical significance (p = 0.14; table 3). In contrast, the expression of osteopontin was significantly augmented in the hearts of 70 days old LP rats compared to NP rats (table 3). In order to localize the tissue compartment responsible for the increase in osteopontin expression, immunohistochemistry for osteopontin in the myocardium was performed. While in neonate heart tissue no differences in staining patterns between NP and LP rats were observed (figure 3), osteopontin immunohistochemistry in the hearts of rats at day 70 of life revealed a distinct staining of the media of myocardial vessels in LP animals which was not detected in NP animals (figure 3).

Bottom Line: The offspring was reduced to six males per litter.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany. carlos.menendez-castro@uk-erlangen.de

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.

Show MeSH
Related in: MedlinePlus