Early and Late Postnatal Myocardial and Vascular Changes in a Protein Restriction Rat Model of Intrauterine Growth Restriction

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.

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

“…As reported previously (10), male offspring of dams fed a low protein diet during pregnancy (LP rats (rats with IUGR)) showed significantly lower birth weights (4.90 ± 0.5 g in LP vs. 6.39 ± 0.34 g in NP rats (control rats), P < 0.001). Body weights remained reduced in LP animals until day 70 of life (365.8 ± 6.6 g in LP rats vs. 383.7 ± 4.4 g in NP rats, P < 0.05).…”

“…For this age, cohort clinical studies could show significant alterations of myocardial structure and functionality after IUGR (6). Contrary to a number of other IUGR models, the impaired myocardial function in our study occurs independently from arterial hypertension and can therefore be considered as a primary IUGR-induced effect (10,12), which may favor the development of cardiac disease later in life. Concerning the relationship between arterial hypertension and IUGR induced by maternal protein restriction, differing reports can be found showing blood pressure elevation (13) or, alternatively, also unaffected blood pressures levels (14).…”

“…In this study, IUGR was induced by maternal protein restriction. According to our observations in this model, no hypertension, no hypercholesteremia, and no atherosclerosis were detected at the time points investigated (10). On the other hand, we observed a moderate increase in myocardial collagen deposition, which was, however, not accompanied by overt myocardial fibrosis or hypertrophy (10).…”

“…Costaining for the fibroblast marker vimentin and α-SMA as marker for myofibroblasts confirmed that the increased number of fibroblasts did not reflect an accumulation of myofibroblasts after IUGR. Nevertheless, an increased number of cardiac fibroblasts may be responsible for the altered myocardial matrix composition in IUGR rats observed in a previous study (10) and may thus alter myocardial elasticity.…”

“…85-23, revised 1996) and were approved by local government authorities (Regierung von Mittelfranken, AZ #54-2531.31-12/06). As described previously, IUGR was induced using the rat model of maternal protein restriction during pregnancy (10). After spontaneous delivery, body weights of the offspring were assessed, and the litters were reduced to six male pups per dam as described (36) to achieve equal lactation conditions.…”