Aims: Carbon dioxide (CO2) has been long known to regulate blood flow and is applied therapeutically in intensive care units to treat brain injury, as well as in balneotherapy for peripheral arterial disease (PAD) and diabetic angiopathy; however, its mode of action remains unclear.
Methods and Results: The vasoactive CO2 effects were tested in arteries of healthy C57BL/6J mice, hypertensive apolipoprotein E-deficient mice, and soluble guanylyl cyclase (sGC) knockout mice in a small vessel myograph with and without pharmacologically intervening in endothelium- and/or vascular smooth muscle-mediated vasodilation. CO2-based Near Infrared Spectroscopy (NIRS-CO2) was developed to test vasoreactivity of the skin microcirculation to CO2 in healthy individuals and PAD and coronary artery disease patients and was benchmarked against flow-mediated dilation (FMD). We identified CO2 as a triple vasodilator mimicking the actions of endothelium-derived relaxing factor (nitric oxide, NO), endothelium-derived hyperpolarization factor (EDHF), and direct myogenic vasodilators. CO2 engaged endothelial NO/sGC and small-/intermediate-conductance calcium-activated potassium channels (SKCa/IKCa), and myogenic voltage-gated (KV) and IKCa potassium channels, respectively, to induce vasodilation hence constituting a bona fide universal vascular hyperpolarizing factor. CO2 responses were reduced and delayed in diseased human and mouse arteries, and NIRS-CO2 reliably predicted microvascular dysfunction in patients with PAD and coronary artery disease. NIRS-CO2 was superior to FMD as it assessed not only endothelial but also myogenic dysfunction. Duration and extent of CO2 vasodilation was coupled to tissue metabolism through vascular carbonic anhydrases (CAs) providing a mechanism for vasculometabolic coupling and one for clinically approved CA inhibitors.
Conclusion: NIRS-CO2 may prove helpful for early detection of vascular dysfunction in cardiovascular, diabetic, vasospastic, and autoimmune angiopathies, whereas fully exploring CO2's therapeutic potential may offer further options in treating vascular diseases.
