Effect of Maternal Protein Restriction in Rats on Cardiac Fibrosis and Capillarization in Adulthood

Abstract

This study examines the effect of maternal protein restriction in rats on levels of cardiac fibrosis, myocardial capillarization, and media:lumen ratio of intramyocardial arteries in adult offspring. Female Wistar Kyoto rats were fed either a normal protein diet (NPD; 20% casein) or a low-protein diet (LPD; 8.7% casein) during pregnancy and lactation. Female offspring (seven per group) were weaned at 4 wk of age and grown to adulthood. At 24 wk of age, the offspring were perfusion fixed. Cardiac fibrosis and media:lumen ratio of intramyocardial arterioles was assessed using image analysis and cardiac capillarization was stereologically investigated. Body weights at 2 and 24 wk of age were significantly reduced (31% and 8%, respectively) in the LPD offspring; however, heart size was not different at 24 wk. Importantly by adulthood, there was a significant 15% increase in left ventricular interstitial fibrosis in LPD offspring. There were no differences in levels of perivascular fibrosis, myocardial capillarization, or in the media:lumen ratio of intramyocardial arteries between groups. Because cardiac fibrosis is associated with impaired cardiac contractility and arrhythmia, our results suggest that induction of interstitial fibrosis may contribute to the increased cardiac disease in adult subjects who were exposed to an adverse intrauterine environment. M any epidemiologic studies have shown that subjects exposed to perturbations in early development have an increased incidence of cardiovascular disease later in life (1-3). It is likely that an adverse intrauterine environment may permanently reduce the numbers of cells/functional units in vital organs, which in turn will affect postnatal organ function. Recent experimental studies of reduced nephron endowment in kidneys, as a result of maternal protein restriction, and subsequent detrimental effects on renal function later in life support this concept (4); whether this is the case in the heart has not yet been elucidated. Interestingly in a recent study in our laboratory, we found that maternal protein restriction throughout pregnancy in rats leads to a reduced heart size and a concomitant decrease in the number of cardiomyocytes (5). Because cardiomyocytes in general cease proliferating soon after birth, with postnatal growth of the heart predominantly due to cardiomyocyte hypertrophy (6), these findings could have important adverse implications on the structure and function of the heart later in life. We postulate that a decrease in the total number of cardiomyocytes in neonatal hearts will limit the capacity for physiologic cardiac growth in adulthood. We propose that when cardiomyocytes reach their limits of hypertrophy, further enlargement of the heart will then occur through increased deposition of extracellular matrix leading to cardiac fibrosis.Indeed, accumulation of extracellular matrix structural proteins in the heart adversely affects myocardial viscoelasticity (7,8) with accumulation of fibrillar collagen leading to cardiac dysfunction (9...

Intrauterine growth restriction coupled with hyperglycemia: effects on cardiac structure in adult rats

“…The relative increase in heart size in the LPD offspring is probably the result of increased collagen deposition within the myocardium; there was a marked increase in interstitial fibrosis within the myocardium of the IUGR offspring. These findings are in accordance with previous findings in our laboratory; earlier, we observed a 15% increase in interstitial fibrosis in the hearts of LPD offspring at 24 wk of age (16). A similarly significant increase in interstitial fibrosis has been described in adolescent guinea pigs that were growth restricted in utero because of chronic placental insufficiency (27).…”

“…In animal models, there is clear evidence of cardiac programming in IUGR offspring as a result of prenatal hypoxia (15). In the rodent maternal protein restriction model, previous studies have shown increased collagen deposition in the hearts of IUGR offspring by early adulthood (24 wk of age) (16) and overt cardiac dysfunction in these animals by 40 wk of age (17). Therefore in this study we proposed that IUGR acts as an initial insult to the developing heart, rendering it more vulnerable to secondary postnatal insults.…”

IUGR in the Absence of Postnatal “Catch-Up” Growth Leads to Improved Whole Body Insulin Sensitivity in Rat Offspring

“…Importantly, our dietary regime of maternal protein restriction differs from many other laboratories in that the rat dams were administered the LPD for 2 wk before mating, throughout pregnancy and for 2 wk during lactation (6,7,12). Indeed, there have been a number of recent studies demonstrating the importance of not only the intrauterine environment but also the periconceptional and lactational environment in determining the long-term growth profile of the offspring (24 -27).…”

“…From 24 wk of age, animals were housed individually for measurement of dietary intake. At 32 wk of age, the rats were perfusion fixed (12). The pancreas and visceral fat (epididymal and intra-abdominal) were excised and weighed.…”

Effect of Maternal Protein Restriction During Pregnancy and Lactation on the Number of Cardiomyocytes in the Postproliferative Weanling Rat Heart

“…The female rats were divided into two groups and fed either a normal-protein diet (NPD) that contained 20% casein or a low protein diet (LPD) that contained 8.7% casein for 2 weeks before mating (to familiarize the dams to the diets), during pregnancy, and 2 weeks after birth (as cardiomyocytes continue to proliferate in the first 2 weeks postnatally in rats) (Lim et al, 2006). After this time, all dams were fed normal laboratory chow.…”