Implication of RAS in Postnatal Cardiac Remodeling, Fibrosis and Dysfunction Induced by Fetal Undernutrition

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.

Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling

“…Besides, a lower expression/immunoreactivity of AT2 receptor was observed in the mesenteric artery of MUN rats, which is in line with data previously reported in the kidney of offspring exposed to maternal undernutrition and low protein diet [34,35], hypoxia [32], GC [36] and our previous report on intramyocardial arteries [15]. Additionally, a lower expression/immunoreactivity for Mas and MrgD receptors were also observed in mesenteric arteries from MUN rats.…”

“…Elevated ACE2 can be interpreted as a compensatory mechanism in response to an increase in Ang II levels, by raising its degradation into Ang 1-7, as previously proposed [8]. In fact, in young MUN rats, we have evidenced increased Ang II plasma levels [15]. In addition, previous work provided evidence that increased vascular ACE leads to increased local Ang II formation [20,21] and the vascular expression of ACE and ACE2 enzymes have been proposed as indicators of local Ang II levels [20,22].…”

“…Similarly, increased pulmonary AT 1 receptor expression was found in lungs of mice exposed to hypoxia [31] and in the kidney of near-term ovine fetuses exposed to high altitude [32]. We have also observed larger AT 1 receptors in intramyocardial arteries from MUN rats in young age [15].…”

“…Adventitial fibroblasts have been shown to produce substantial amounts of NADPH oxidase-derived ROS in response to vascular injury or vasoactive substances, and play an active role in collagen deposition and vascular remodeling [41]. We have gathered previous evidence on increased collagen, associated with elevation of AT1 receptors in intramyocardial arteries from MUN rats [15]. Among them, Ang II is recognized as one of the key humoral factors implicated in NADPH oxidase activation in the vascular wall [42][43][44].…”

“…In several animal models of the fetal programming of hypertension (FPH), BP rise is controlled by treatment with ACE inhibitors or Ang II receptor antagonists [10][11][12] similar to what occurs in essential hypertension. On the other hand, we have previously shown that in an animal model of FPH induced by maternal undernutrition, cardiac remodeling is related to oxidative stress [13,14], a misbalance in cardiac RAS receptors in early life (rats with 21 days: [15], and facilitation of prejunctional AT 1 receptors (in vascular sympathetic nerve terminals) mediated by an augmented locally generated Ang II [16]. These data point out at the possible role of vascular RAS in FPH.…”