NEONATAL EXPOSURE TO HIGH OXYGEN LEVELS IS ASSOCIATED WITH IMPAIRED ISCHEMIA-INDUCED NEOVASCULARIZATION DURING ADULTHOOD

Abstract

It is increasingly recognized that neonatal conditions, including prematurity, can significantly modulate adult cardiovascular health. Premature 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. Neovascularization is an essential defense mechanism against ischemic vascular diseases. Here we tested the novel hypothesis that neonatal exposure to high oxygen levels might impair ischemia-induced neovascularization in the adult. C57BL/6 mice were exposed to hyperoxia (80% O2) or normoxia (20% O2) from days 2 to 14 after birth. Mice from both groups remained in normoxic conditions thereafter. When the mice reached adulthood (6-8 weeks), hindlimb ischemia was surgically induced by femoral artery removal. We found that neonatal hyperoxia was associated with a significantly slower rate of blood flow recovery after hindlimb ischemia, as assessed by Laser Doppler imaging. Doppler flow ratios were significantly reduced in mice exposed to neonatal hyperoxia, both at day 7 (0.41+/-0.04 vs. 0.65+/-0.08; p<0.05) and at day 21 (0.51+/-0.05 vs. 0.72+/-0.03; p<0.05) after surgery. At the microvascular level, neonatal hyperoxia led to a significant decrease of capillary density in ischemic muscles (98.78+/-6.84 vs. 160.9+/-13.58; p<0.001). Clinically, this was associated with an increased hindlimb ischemic damage in mice exposed to neonatal hyperoxia. Endothelial progenitor cells (EPCs) have been shown to have an important role for postnatal neovascularisation. In adult mice, we found that previous neonatal exposure to hyperoxia was associated with a reduced number of bone marrow EPCs at day 7 after hindlimb ischemia. Moreover, the migration properties of EPCs were significantly impaired in mice exposed to neonatal hyperoxia. Interestingly, aortic endothelial cells (MAECs) isolated from mice that had been exposed to neonatal hyperoxic conditions appear to exhibit reduced migration capacity compared to MAECs isolated from control mice. Transient neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization during adulthood. The mechanism involves negative effects of neonatal hyperoxia on angiogenic pathways in ischemic muscles, together with a decrease in EPC number and function.