Abstract
Fetal undernutrition is a risk factor for cardiovascular diseases. Male offspring from rats exposed to undernutrition during gestation (MUN) exhibit oxidative stress during perinatal life and develop cardiac dysfunction in ageing. Angiotensin-II is implicated in oxidative stress-mediated cardiovascular fibrosis and remodeling, and lactation is a key developmental window. We aimed to assess if alterations in RAS during lactation participate in cardiac dysfunction associated with fetal undernutrition. Control dams received food ad libitum, and MUN had 50% nutrient restriction during the second half of gestation. Both dams were fed ad libitum during lactation, and male offspring were studied at weaning. We assessed: ventricular structure and function (echocardiography); blood pressure (intra-arterially, anesthetized rats); collagen content and intramyocardial artery structure (Sirius red, Masson Trichromic); myocardial and intramyocardial artery RAS receptors (immunohistochemistry); plasma angiotensin-II (ELISA) and TGF-β1 protein expression (Western Blot). Compared to Control, MUN offspring exhibited significantly higher plasma Angiotensin-II and a larger left ventricular mass, as well as larger intramyocardial artery media/lumen, interstitial collagen and perivascular collagen. In MUN hearts, TGF-β1 tended to be higher, and the end-diastolic diameter and E/A ratio were significantly lower with no differences in ejection fraction or blood pressure. In the myocardium, no differences between groups were detected in AT1, AT2 or Mas receptors, with MrgD being significantly lower in the MUN group. In intramyocardial arteries from MUN rats, AT1 and Mas receptors were significantly elevated, while AT2 and MrgD were lower compared to Control. Conclusions. In rats exposed to fetal undernutrition, RAS disbalance and associated cardiac remodeling during lactation may set the basis for later heart dysfunction.
Highlights
In a rat model of fetal programming induced by undernutrition (MUN rat), we have observed that catch-up growth affects cardiovascular organs; male rats exposed to undernutrition are born with a smaller aorta, which is enlarged during lactation [10]
Since oxidative stress plays a central element in cardiac hypertrophy and fibrosis in the context of elevated Angiotensin II (Ang II), through the activation of NADPH oxidase [44,48], we suggest that oxidative damage could be a potential mechanism implicated in the Ang-II mediated pathological responses observed in the heart from Maternal Undernutrition (MUN)
Further studies are needed to analyze the potential of RAS blockade in early stages of life as a therapeutic target in low birth weight (LBW) individuals with high risk of cardiovascular diseases (CVD)
Summary
Epidemiological studies evidence that exposure to an adverse intrauterine environment, such as sub-optimal nutrition, leading to low birth weight (LBW), is associated with increased risk of cardiovascular diseases (CVD), a process known as fetal programing [1]. Studies in LBW children have demonstrated that catch-up growth increases the risk of developing cardio-metabolic diseases later in life [5,6,7]. There is evidence that catch-up growth during lactation has deleterious consequences, leading to adipose tissue accumulation [8,9]. In a rat model of fetal programming induced by undernutrition (MUN rat), we have observed that catch-up growth affects cardiovascular organs; male rats exposed to undernutrition are born with a smaller aorta, which is enlarged during lactation [10]
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