Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea

Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded, and subjected to constant oxygenation (1%, 4%, 13% or 20% O₂) or IH at different frequencies (0.6, 6 or 60 cycles/h) and magnitude ranges (13-4% O₂ or 20-1% O₂) using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O₂ and 13% O₂, but was considerably increased (up to 2-fold) in constant hypoxia (4% and 1% O₂). The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13%-4% O₂ at mild frequencies (0.6 and 6 cycles/h) accelerated endothelial wound healing by 115% and 88%, respectively. However, for IH exposures consisting of 20% to 1% O₂ oscillations, wound closure was reduced compared to oscillation in the 13%-4% range (by 59% and 51% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA.

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