Transient Neonatal Exposure to High Oxygen Levels is Associated With Impaired Ischemia-induced Neovascularization During Adulthood

Introduction: Deleterious perinatal conditions, including preterm birth, can lead to developmental programming of cardiovascular diseases. Prematurely born infants are often exposed to high oxygen levels, which in animal models has been associated with the adult development of endothelial dysfunction, hypertension, and cardiac remodeling. Here we tested the novel hypothesis that neonatal exposure to hyperoxia might impair ischemia-induced neovascularization in the adult. Methods and Results: C57Bl/6 newborn mice were kept with their mother in 85% O 2 or room air (control) from day 2 to 14 after birth. When the mice reached adulthood (6-8 weeks), hindlimb ischemia was surgically induced by femoral artery removal. Neonatal exposure to O 2 was not associated with hypertension in adult mice. However mice exposed to O 2 after birth showed a significant impairment of blood flow recovery after hindlimb ischemia, as assessed by Laser Doppler imaging at day 7 and 21 after surgery. Clinically, this was also associated with increased hindlimb ischemic damages. At the microvascular level, neonatal hyperoxia was associated with a significant decrease of capillary density in ischemic muscles. Moreover, ischemic muscles isolated from mice exposed to O 2 exhibited increased oxidative stress levels (DHE staining), together with a reduced expression of superoxide dismutase 1 (SOD1) and vascular endothelial growth factor (VEGF), as assessed by Western blotting. Pro-angiogenic cells (PACs) have been shown to have an important role for postnatal neovascularisation. Here we found that neonatal exposure to O 2 is associated with a significantly reduced number of central (bone marrow) and peripheral PACs in adults. Interestingly, the functional/angiogenic activities of both PACs and mature mouse aortic endothelial cells (MAECs) are significantly impaired in mice that have been exposed to O 2 after birth. Conclusions: Transient neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization during adulthood. The mechanism involves negative effects of neonatal hyperoxia on oxidative stress levels and angiogenic signals in ischemic muscles, together with defective functional activities of PACs and mature endothelial cells.