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Capillary Oxygen Triggers Conducted Hyperpolarization and Dilation Independent of Extracellular K + and Endothelial K IR 2.1
Author(s) -
Kowalewska Paulina M.,
Milkovich Stephanie,
Ellis Christopher G.,
Welsh Donald G.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04196
Subject(s) - chemistry , biophysics , hematocrit , connexin , microcirculation , gap junction , capillary action , extracellular , oxygen , medicine , anatomy , biochemistry , biology , materials science , intracellular , organic chemistry , composite material
The matching of red blood cell (RBC) supply to oxygen demand is an intricate process which requires generation of a capillary stimulus and triggering of a transduction process that dilates upstream arterioles. The sensor’s identity, the stimulus it generates and the mechanisms that enables it are openly debated and a source of active inquiry. This study tested whether extracellular K + is the stimulus and if capillary K IR 2.1 channels enable upstream arteriolar dilation via conduction. Experiments were performed in vivo, using a live microcirculatory preparation (extensor digitorum longus); the local oxygen environment was tightly controlled (custom stage insert) and capillary RBC kinetics monitored in mice lacking endothelial K IR 2.1 or connexin 40. Dropping PO 2 on the muscle surface (53 mmHg to 15 mmHg or 0 mmHg (3 min)) induced a stark microvascular response in control animals (RBC supply rate, velocity and hematocrit increased by 56%, 28% an 18%, respectively) without diminishing mitochondrial respiration. This blood flow response failed to materialize in connexin 40 −/− mice. As this response was absent, capillary RBC O 2 saturation was lower under normal conditions in the connexin 40 −/− animals. In contrast, endothelial K IR 2.1 −/− mice reacted normally to O 2 challenges, with RBC supply rate, velocity and hematocrit rising by 43%, 28%, and 11%, respectively. These findings show that coupling O 2 demand‐to‐O 2 supply requires coordinated electrical signaling among cells connected by gap junctions comprised of connexin 40. They also show that endothelial K IR 2.1 channels are not responsible for initiating the hyperpolarization needed to drive conduction. These findings begin the process of restructuring our understanding of blood flow regulation and how O 2 initiates this process independent of metabolite production. Support or Funding Information This work was funded by NSERC Discovery grants to CGE and to DGW.