Daniela Ravizzoni Dartora, Université de Montréal
Supervisor: Anne Monique Nuyt, Université de Montréal
Nearly 10% of Canadian children are born preterm each year. Improvements in neonatal intensive care have resulted in survival of the vast majority of these infants. Preterm birth results in ex utero development of an immature cardiovascular system. Studies now support a direct causal association between preterm birth and adverse changes in cardiovascular structure and function, which persist into adulthood, and are associated with hypertension, metabolic disorders and stroke. Clinical and experimental studies have shown how preterm birth and the pro- inflammatory and pro-oxidative nature of its related conditions (such as O2 toxicity), contribute to altered cardiac development (hypertrophy, fibrosis), vascular dysfunction, defective vascular growth with small vessels rarefaction and activation of the renin-angiotensin system (RAS) which are all involved in the programming of hypertension and enhanced susceptibility to heart failure reported in preterm born subjects and animal models.
Key to the development of all organ systems is angiogenesis and vascular repair, which are driven by circulating endothelial progenitor cells (EPCs). Dysfunctional EPCs (decreased count and/or impaired function) are closely linked to cardiovascular diseases (CVD) risk factors and progression. Chronic inflammation and oxidative stress, as in hypertension and metabolic disorders, contribute to impair EPCs whereas interventions such as exercise and RAS inhibitor improve EPCs in patients with CVD. Interestingly, disorders of pregnancy such as diabetes and pre- eclampsia, characterized by inflammation and oxidative stress, adversely alter EPCs in the newborn. Further, emerging experimental data suggest that circulating EPCs are impaired in the cord blood of preterm neonates and correlate with the development of complications of prematurity (such as bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted vascular development). Taken together, these studies suggest that impaired EPCs could underline many of the short and long-term cardiovascular complications associated with preterm birth. However, studies beyond the neonatal period are currently lacking.
The overall postulate of this proposal is that preterm birth alters circulating EPCs count and function in adulthood, particularly ECFCs (endothelial colony forming cells, a subgroup of cells with greater proliferative and angiogenic capacity), through dysregulation of the renin angiotensin system and that impaired EPCs correlate with the altered cardiovasculature of preterm individuals.
To tackle this hypothesis, we propose a translational research program that combines a clinical study of young adults born extremely preterm (PT; <29 wks gestational age) vs. term (T), and a well-recognized experimental rodent model of preterm birth related conditions (neonatal exposure to hyperoxia). The lifetime approach to CVD prevention emphasizes the importance of studying the impact of adverse fetal and neonatal events on developmental physiological mechanisms that may lead to later pathology. Understanding these processes will have great implications in terms of development of biomarkers for early identification of disease risk in preterm infants during the neonatal period and beyond, and advances in therapeutic interventions.