Abstract
Adverse perinatal conditions 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 endothelial dysfunction, hypertension, and cardiac remodeling during adulthood. Here we found that adult mice that have been transiently exposed to O2 after birth show defective neovasculariation after hindlimb ischemia, as demonstrated by impaired blood flow recovery, reduced vascular density in ischemic muscles and increased tissue damages. Ischemic muscles isolated from mice exposed to O2 after birth exhibit increased oxidative stress levels and reduced expression of superoxide dismutase 1 (SOD1) and vascular endothelial growth factor (VEGF). Pro-angiogenic cells (PACs) have been shown to have an important role for postnatal neovascularisation. We found that neonatal exposure to O2 is associated with reduced number of PACs in adults. Moreover, the angiogenic activities of both PACs and mature mouse aortic endothelial cells (MAECs) are significantly impaired in mice exposed to hyperoxia after birth. Our results indicate that neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization during adulthood. The mechanism involves deleterious effects on oxidative stress levels and angiogenic signals in ischemic muscles, together with dysfunctional activities of PACs and mature endothelial cells.
Highlights
Increasing evidence suggests that adverse perinatal events can induce developmental programming of future diseases during adulthood, in the cardiovascular system[1,2]
After surgery, Laser Doppler flow ratios (DFR) between the ischemic and normal hindlimbs reached comparable low levels, indicating that the severity of the ischemia was similar in the 2 groups (Fig. 1B)
The present study is the first documentation of the negative effect of neonatal hyperoxia on ischemia-induced neovascularization during adulthood
Summary
Increasing evidence suggests that adverse perinatal events can induce developmental programming of future diseases during adulthood, in the cardiovascular system[1,2]. Infants born preterm are often exposed to high concentrations of O2, especially when compared to the relative hypoxic condition of the intrauterine life[4] This can lead to increased oxidative stress[5], a factor that is thought to be involved in several diseases of prematurity including retinopathy and bronchopulmonary dysplasia[6]. Conditions leading to the development of atherosclerosis and vascular occlusions in patients are often associated with impaired neovascularization in response to ischemia[9] Cardiovascular risk factors such as aging, cigarette smoke exposure, diabetes and hypercholesterolemia have been associated with impaired ischemia-induced neovascularization and reduced number of PACs, both in animal models and in humans[9,17]. We investigated potential mechanisms involved in that pathophysiology, including the effects of perinatal hyperoxia on the functional activities of mature endothelial cells and PACs
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