Science, Medicine, and the Anesthesiologist

Tissue oxygen delivery requires localized sensing of oxygen demand that dictates upstream arteriolar dilation. Microvascular blood flow is closely matched to tissue oxygen requirements and under current theory is believed to involve parenchymal tissue hypoxia, which induces accumulation of extracellular K+, which diffuses to activate endothelial inwardly rectifying K+ channels (K_IR2.1) to induce arteriolar dilation; however, this theory does not account for the required precise temporal and spatial control of microvascular blood flow. The microphysiologic control of capillary blood flow was studied using in vivo imaging of capillary blood flow while manipulating tissue and red blood cell oxygen in skeletal muscle of transgenic mouse models lacking the endothelial K_IR2.1 channel or the connexin 40 protein of cellular gap junctions. Results demonstrate that oxygen responses are generated in capillaries as opposed to tissue parenchyma and require electrical conduction via connexin40 proteins to upstream arterioles to control blood flow without the involvement of the K_IR2.1 channel. This indicates that connexin-mediated electrical conduction is pivotal in modulating oxygen supply and demand at the capillary level. This is controlled by endothelial cell hyperpolarization communicating through gap junctions with upstream endothelial and vascular smooth muscle cells to dilate arterioles to allow for increased capillary red blood cell supply.