Capillary Oxygen Triggers Conducted Vasodilation via Connexin 40 Independent of Extracellular K ⁺ and Endothelial K _IR 2.1

Mechanisms that fine‐tune red blood cell (RBC) and O 2 delivery to capillaries are critical to tissue function. Coupling RBC supply to demand is an intricate process requiring O 2 sensing, generation of a capillary stimulus and triggering of a transduction process that alters the diameter of upstream arterioles. The sensor's identity, the stimulus it generates and the mechanisms that enable it are actively debated. Studies have implied the endothelial K IR 2.1 channels drive O 2 sensing whereas gap junctions, comprised of connexin 40, enable electrical signals to conduct upstream. This idea was tested in K IR 2.1 ‐/‐ and connexin 40 ‐/‐ mice where the local O 2 environment of skeletal muscle was precisely controlled. The extensor digitorum longus muscle was prepared for intravital microscopy; a custom stage insert with a gas chamber allowed for O 2 control at the tissue surface. Second‐by‐second capillary RBC flow responses were recorded as O 2 was: 1) reduced from 53 mmHg to 15 mmHg or 0 mmHg for 3 min; or 2) oscillated between 91 mmHg and 15 mmHg (1 cycle/min). Chamber O 2 at 15 mmHg induces microvascular responses without diminishing mitochondrial function while 0 mmHg initiates additional metabolic responses. Dropping PO 2 on the muscle surface (53 mmHg to 15 mmHg or 0 mmHg) significantly increased RBC supply rate in capillaries of control animals while elevated chamber O 2 decreased capillary RBC supply rate in a graded manner. The RBC flow responses in control mice were rapid and tightly coupled to O 2 levels as the chamber O 2 was oscillated in a sinusoidal fashion. In stark contrast, this blood flow response failed to occur in connexin 40 ‐/‐ mice. As this response was absent, capillary RBC O 2 saturation was lower under resting conditions in the connexin 40 ‐/‐ animals. Endothelial K IR 2.1 ‐/‐ mice, on the other hand, had normal resting RBC O 2 saturation. Furthermore, K IR 2.1 ‐/‐ mice reacted normally to O 2 changes, albeit an oscillation or a sustained O 2 decrease (to 15 mmHg), with a rise in RBC supply rate. Likewise, the microcirculatory response to 0 mmHg O 2 was similar between floxed control and endothelial K IR 2.1 ‐/‐ mice. We show that microvascular O 2 responses depend on coordinated electrical signaling via gap junctions comprised of connexin 40 and that endothelial K IR 2.1channels do not drive the initiating electrical event. These findings reform our understanding of blood flow regulation and how O 2 initiates this process independent of metabolite production.

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