Transient Neonatal High Oxygen Exposure Leads to Early Adult Cardiac Dysfunction, Remodeling, and Activation of the Renin–Angiotensin System

Abstract

Abstract-Perinatal conditions (such as preterm birth) can affect adult health and disease, particularly the cardiovascular system. Transient neonatal high O 2 exposure in rat in adulthood (a model of preterm birth-related complications) leads to elevated blood pressure, vascular rigidity, and dysfunction with renin-angiotensin system activation. We postulate that neonatal hyperoxic stress also affects myocardial structure, function, and expression of renin-angiotensin system components. Sprague-Dawley pups were kept with their mother in 80% O 2 or in room air (control) from days 3 to 10 of life. Left ventricular function was assessed in 4-, 7-, 12-week-old (echocardiography) and in 16-week-old (intraventricular catheterization) male O 2 -exposed versus control rats. At 16 weeks, hearts from O 2 -exposed rats showed cardiomyocyte hypertrophy, enhanced fibrosis, and increased expression of transforming growth factor-β1, senescence-associated proteins p53 and Rb, upregulation of angiotensin II type 1 (AT1) receptor expression (protein and AT1a/b mRNA), and downregulation of AT2 receptors. At 4 weeks (before blood pressure increase), the expression of cardiomyocyte surface area, fibrosis, p53, and AT1b was significantly increased and AT2 decreased in O 2 -exposed animals. After 4 weeks of continuous angiotensin II infusion (starting at 12 weeks), O 2 -exposed rats developed severe heart failure, with impaired myocardial mechanical properties compared with saline-infused rats. Transient neonatal O 2 exposure in rats leads to left ventricular hypertrophy, fibrosis and dysfunction, and increased susceptibility to heart failure under pressure overload. These results are relevant to the growing population of individuals born preterm who may be at higher risk of cardiac dysfunction when faced with increased peripheral resistance associated with hypertension, vascular diseases, and In cardiovascular disease, RAS plays a major role in vascular dysfunction, cardiac hypertrophy, and fibrosis through Ang II acting predominantly on its type I receptor (AT1) 10,11 triggering downstream mechanisms such as the profibrotics transforming growth factor-β1 (TGF-β1) and hypoxic-inducible factor-1α (HIF-1α), 12 as well as senescence-associated pathways. 13Activation of the RAS in the kidneys, brain, and systemic vasculature plays a key role in the elevation and maintenance of BP in experimental models associated with deleterious perinatal conditions including transient neonatal high O 2 exposure. 6,14 However, the effect of neonatal pro-oxidant conditions on cardiac RAS components has not been reported. To determine whether neonatal hyperoxia exposure impaired cardiac development and predisposed to cardiac dysfunction, myocardial structure, and function, expression of cardiac RAS components, as well as TGF-β1, HIF-1α, and senescenceassociated proteins, was determined in young, 4-week-old, and adult, 16-week-old rats infused or not with Ang II. Materials and MethodsSprague-Dawley pups were kept with their mother in 80% O 2 using an oxyc...

Endothelial Colony‐Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease

“…In addition, the mechanisms linking hypertension and ECFC dysfunction are still unknown. Beyond the hypothesis of a cause/effect relationship between ECFC dysfunction and elevated blood pressure, ECFC dysfunction and hypertension may result from common physiopathological pathways, such as the activation of the autonomic nervous system, renin–angiotensin system, and inflammation,45 which in turn were all previously shown to be altered in preterm‐born subjects or in experimental models of preterm birth 46, 47, 48, 49, 50, 51, 52, 53. These observations suggest that both ECFC dysfunction and elevated blood pressure could be long‐term consequences of very preterm birth.…”

Endothelial colony-forming cell therapy for heart morphological changes after neonatal high oxygen exposure in rats, a model of complications of prematurity

“…2014, 2016). Perivascular fibrosis was also increased, which we had not assessed in our previous studies.…”

“…2008; Bertagnolli et al. 2014, 2016). In the present study, we did not observe the slight increase in heart to body weight index in O 2 ‐exposed animals reported previously (Bertagnolli et al.…”

“…In the present study, we did not observe the slight increase in heart to body weight index in O 2 ‐exposed animals reported previously (Bertagnolli et al. 2014, 2016). However, comparable to current findings, a recent study using a similar neonatal hyperoxia model showed no difference in cardiac hypertrophy index at 1 year (Goss et al.…”

“…2008; Bertagnolli et al. 2014, 2016). Beyond the lungs, neonatal hyperoxia affects vascular development in the retina and in peripheral striated muscles (Yzydorczyk et al.…”