Abstract
The systemic response to decreasing oxygen levels is hypoxic vasodilation. While this mechanism has been known for more than a century, the underlying cellular events have remained incompletely understood. Nitrite signaling is critically involved in vessel relaxation under hypoxia. This can be attributed to the presence of myoglobin in the vessel wall together with other potential nitrite reductases, which generate nitric oxide, one of the most potent vasodilatory signaling molecules. Questions remain relating to the precise concentration of nitrite and the exact dose-response relations between nitrite and myoglobin under hypoxia. It is furthermore unclear whether regulatory mechanisms exist which balance this interaction. Nitrite tissue levels were similar across all species investigated. We then investigated the exact fractional myoglobin desaturation in an ex vivo approach when gassing with 1% oxygen. Within a short time frame myoglobin desaturated to 58±12%. Given that myoglobin significantly contributes to nitrite reduction under hypoxia, dose-response experiments using physiological to pharmacological nitrite concentrations were conducted. Along all concentrations, abrogation of myoglobin in mice impaired vasodilation. As reactive oxygen species may counteract the vasodilatory response, we used superoxide dismutase and its mimic tempol as well as catalase and ebselen to reduce the levels of reactive oxygen species during hypoxic vasodilation. Incubation of tempol in conjunction with catalase alone and catalase/ebselen increased the vasodilatory response to nitrite. Our study shows that modest hypoxia leads to a significant nitrite-dependent vessel relaxation. This requires the presence of vascular myoglobin for both physiological and pharmacological nitrite levels. Reactive oxygen species, in turn, modulate this vasodilation response.
Highlights
Hypoxic vasodilation is one of the key adaptive responses to maintain an equilibrium between oxygen (O2) supply and demand for e.g. muscle tissue at work [1]
Many different mechanisms have been proposed to contribute to these processes including adenosine, pH changes, prostacyclin and potassium [5,6,7,8]
Prior to assessing the dose-dependent effects of Mb-related nitrite reduction on vessel dilation under hypoxia, we set out to test whether exposure to a generally-acknowledged hypoxia level leads to a significant Mb desaturation
Summary
Hypoxic vasodilation is one of the key adaptive responses to maintain an equilibrium between oxygen (O2) supply and demand for e.g. muscle tissue at work [1]. The observation that vessels dilate when subjected to decreasing O2 tensions was made more than 150 years ago, the underlying signal transduction mechanisms have remained under intensive debate [2,3]. This pertains both to the O2 sensor as well as to the coupled vasodilatory effector signaling. It is generally believed that upon reaching a critical O2 saturation, a sensor mechanism transmits this event to a cellular signaling cascade, which decreases the levels of intracellular [Ca2+] with subsequent relaxation of the vascular smooth muscle machinery [4]. The exact nature of the vasodilatory mechanism, remained unresolved
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