Local mechanisms, that act upon the microvasculature, control blood flow to various organs to meet their metabolic demands. Oxygen has been implicated in this regulatory process for over a century. However, its precise role in the regulation of blood flow remains unclear because we do not know where changes in PO2 are sensed and how changes in PO2 are coupled to changes in arteriolar muscle tone. Therefore the overall aims of the research proposed are to 1.) Identify the location of the sensor that mediates arteriolar O2 reactivity, and 2.) Establish the mechanism of action of O2 on these microvessels. The focus of this proposal will be on arteriolar O2 reactivity in the microcirculation of skeletal muscle. We are in a unique position to study arteriolar function in this tissue from the level of single ion channels in isolated arteriolar muscle cells in vitro, to responses of intact arterioles in the living microcirculation. More importantly, skeletal muscle represents 40% of body mass and the microcirculation in this tissue contributes substantially to the regulation of blood pressure and cardiovascular homeostasis in general. Finally, disease states, such as hypertension, have been shown to alter the structure of arterioles in skeletal muscle and to modify functions such as O2 reactivity and arteriolar muscle cell electrophysiology in this tissue. Thus, the study of the O2 reactivity of arterioles in this important microcirculation may provide clues to better understand the etiology or consequences of disease states such as hypertension.
The specific aims of the research proposed are to test four hypotheses concerning the site and mechanism of action of O2 on skeletal muscle arterioles. They are: 1) O2 is sensed directly by arteriolar muscle cells, 2.) O2- induced arteriolar constriction is mediated by cytochrome P-450 4a through O2-dependent production of 20-hydorxyeicosatetraenoic acid (20-HETE), 3.)O2 and 20-HETE act to close ATP-sensitive K+ (KATP) channels in arteriolar muscle cells, and 4.) Closure of KATP channels by O2 and 20-HETE depolarizes arteriolar muscle cells which leads to increased Ca++ influx through voltage- activated Ca++ channels and contraction of arteriolar muscle cells. These hypotheses will be tested using techniques ranging from perforated patch recording of K+ currents in single arteriolar muscle cells, to measurement of membrane potential, diameter and periarteriolar PO2 in aparenchymal arterioles in vivo in the cremaster muscle of golden Syrian hamsters.

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National Heart, Lung, and Blood Institute (NHLBI)
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Western Michigan University
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Jackson, William F; Boerman, Erika M (2018) Voltage-gated Ca2+ channel activity modulates smooth muscle cell calcium waves in hamster cremaster arterioles. Am J Physiol Heart Circ Physiol 315:H871-H878
Jackson, William F (2018) KV channels and the regulation of vascular smooth muscle tone. Microcirculation 25:
Jackson, W F (2017) Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth. Adv Pharmacol 78:89-144
Jackson, William F; Boerman, Erika M (2017) Regional heterogeneity in the mechanisms of myogenic tone in hamster arterioles. Am J Physiol Heart Circ Physiol 313:H667-H675
Jackson, William F (2017) Boosting the signal: Endothelial inward rectifier K+ channels. Microcirculation 24:
Jackson, William F (2016) Arteriolar oxygen reactivity: where is the sensor and what is the mechanism of action? J Physiol 594:5055-77
Westcott, Erika B; Goodwin, Erica L; Segal, Steven S et al. (2012) Function and expression of ryanodine receptors and inositol 1,4,5-trisphosphate receptors in smooth muscle cells of murine feed arteries and arterioles. J Physiol 590:1849-69
Westcott, Erika B; Jackson, William F (2011) Heterogeneous function of ryanodine receptors, but not IP3 receptors, in hamster cremaster muscle feed arteries and arterioles. Am J Physiol Heart Circ Physiol 300:H1616-30
Hakim, Chady H; Jackson, William F; Segal, Steven S (2008) Connexin isoform expression in smooth muscle cells and endothelial cells of hamster cheek pouch arterioles and retractor feed arteries. Microcirculation 15:503-14
Brekke, Johan Fredrik; Jackson, William F; Segal, Steven S (2006) Arteriolar smooth muscle Ca2+ dynamics during blood flow control in hamster cheek pouch. J Appl Physiol 101:307-15

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