Mechanisms of Arterial Dilation in Exercise Hyperemia
Keller, Alexander, Pharmacology - School of Medicine, University of Virginia
Isakson, Brant, Molecular Physiology and Biological Physics, University of Virginia
Matching oxygen supply to consumption across different tissues is a critical function of the vasculature. The remarkably wide range of metabolic demand between resting and active skeletal muscle renders control of blood flow to skeletal muscle tissues especially important and challenging. Mechanisms of exercise hyperemia are believed to be multifaceted and redundant, reflecting both the complexity of this response as well as its importance. We explored two candidate mechanisms of exercise hyperemia, examining ATP release from red blood cells and hemoglobin alpha in the endothelium of resistance arteries.
We first studied the participation of Pannexin 1 in a red blood cell pathway reported to link hypoxia to elevated cyclic AMP and finally ATP release via Pannexin 1 to promote vasodilatory signaling in the endothelium. Our findings contradict previous claims that these components participate in the same signaling pathway. Furthermore, our work highlights a number of methodological considerations that we present as best practices for future in vitro work studying ATP release from red blood cells. Finally, we report exercise data that suggests more broadly a lack of significant role for Pannexin 1 in exercise performance.
Subsequently, we hypothesized a novel role for endothelial hemoglobin alpha as a nitrite reductase during hypoxia. This mechanism has received significant attention in red blood cell hemoglobin, but has not previously been examined in the endothelium. Creating novel genetic models of Hba1 deletion, we demonstrated a reduction in exercise performance upon deletion of endothelial Hba1 in mice. These effects appear to be independent of the endothelial Hbα-eNOS interaction previously reported by our laboratory. Preliminary myography data shows impaired dilation of EC Hba1Δ/Δ skeletal muscle resistance arteries in response to hypoxia. We identify further experiments planned to clarify the mechanism underlying these results. Taken together, our findings point to a novel role for endothelial hemoglobin alpha as a critical regulator of skeletal muscle blood flow during exercise.
PHD (Doctor of Philosophy)
exercise hyperemia, hemoglobin alpha, pannexin 1, vasodilation, exercise, exercise physiology, hypoxia, nitric oxide, resistance artery, vascular physiology, vascular, thoracodorsal artery, red blood cell, erythrocyte, hemoglobin, dilation, ATP, hemolysis
National Institutes of HealthAmerican Heart Association
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