Research Summary

Our current research employs a systems biology approach to evaluate the mechanisms by which oxygen supply is matched to oxygen demand in skeletal muscle. Although the idea that flow must be regulated to meet tissue needs is not new, there is little understanding of how this task is actually accomplished. Studies done by students in this laboratory have lead us to what is now our current working hypothesis that the red blood cell, in addition to serving as the primary carrier of oxygen, is itself the sensor and initiator of a conducted vasodilator response via its release of ATP. This vasodilator response is thus able to direct flow to the precise location of need. The red blood cell thus controls its own distribution.

Our laboratory employs a number of diverse physiological and pharmacological approach to dissect out components of this flow distribution mechanism. Using in vivo video microscopy and computer assisted image analysis we are determining red blood cell supply rate and their oxygen saturation in normal muscle and muscles of animals with diabetes. In addition, we are evaluating the effect of low oxygen tension, ATP and EETs on vascular perfusion in both normal and animals with diabetes. In parallel studies using isolated, perfused arterioles we are dissecting out the components of the response and the impact of alterations in the erythrocyte’s ability to release ATP on vasoactivity. An additional question we are trying to address is to determine how the red blood cell is able to sense a change in oxygen content leasing to the release ATP into the extracellular fluid. With the help of collaborators at the University of Western Ontario, we are working to develop a physiological model of the regulation of blood flow distribution to meet tissue needs, a model which would fill the role of the long sought after metabolic regulator of blood flow distribution.

2000               Elected Fellow of the Cardiovascular Section of American Physiological Society

1997-'01         Secretary, Microcirculatory Society

1993-'96         Executive Council, Microcirculatory Society

1992-'96         NIH, Research Career Development Award

1989               IPM, Inc. Innovative Instrumentation Award, Microcirculatory Society

1988-'94         NIH, First Independent Research Support and Transition Award

1984               Young Investigator of the Year, Microcirculatory Society

“Microvascular O₂ Delivery: Impact of Erythrocyte-Released ATP” NHLBI Exploratory Program in Systems Biology (R33) (HL-089094) Lead PD/PI (2007-2011)

"The erythrocyte as a regulator of microvascular perfusion", R01 NHLBI (HL-56249), P.I.: 1997-2007.

"Oxygen affinity and oxygen transport in striated muscle" NHLBI, R01 (HL-39226) P.I.: 1994-1998.

Research Career Development Award, NHLBI, (HL-02602) 1992-1996.

FIRST Award, NHLBI, (HL-39226) P.I.: 1988-1994.

Grant-in-Aid, American Heart Association (MO Affiliate), 1990-1992.

Faculty Grant-in-Aid, Virginia Commonwealth University, 1987-1988.

John B. Foote Foundation, Medical College of Virginia, 1983-1986.

National Research Service Award, Individual Postdoctoral Fellowship, NHLBI (HL-06520), 1982-1985

Publications

Ellsworth, M.L.: The red blood cell as an oxygen sensor: What is the evidence? Acta Physiol. Scand. 168:551-559, 2000.

Sprague, R.S., Ellsworth, M.L., Stephenson, A.H. and Lonigro, A.J.: Red Blood Cell-derived ATP is a Determinant of Nitric Oxide Synthesis in the Pulmonary Circulation. In: “Interactions of Blood and the Pulmonary Circulation”, Weir, E.K., Reeve, H.L., and Reeves, J.T. (Eds), Futura Publishing company, Inc., Armonk, NY, 2002.

Dietrich, H.H., Ellsworth, M.L. and Dacey, Ralph G., Jr.: The red blood cell, ATP and integrated vascular responses to neuronal stimulation. International Congress Series 1235; Elseveir Science, 2002, 277-287.

Sprague, R.S., Ellsworth, M.L. and Dietrich, H.H.: Nucleotide release and purinergic signaling in vasculature driven by the red blood cell. In: “Extracellular Nucleotides and Nucleosides: Release, Receptors, and Physiological & Pathological Effects”; Schweibert, E.M., editor. Elsevier Science, 2003 pp 243-268.

Olearczyk J.J., Ellsworth M.L., Stephenson A.H., Lonigro A.J., Sprague R.S. Nitric oxide inhibits ATP release from erythrocytes. J of Pharm & Exp Ther. 309(3):1079-84, 2004

Ellsworth, M.L.: Red Blood Cell Derived ATP as a Regulator of Skeletal Muscle Perfusion: Med. Sci. Sports Exerc., Vol. 36, No. 1, pp. 35-41, 2004.

Rozier, M.D., Zata, V.J. and Ellsworth, M.L.: Lactate interferes with ATP release from red blood cells. Am J Physiol; Heart Circ Physiol, 292: H3038 - H3042, 2007.

Adderley SP, Dufaux EA, Shridharan M, Bowles EA, Hanson MS, Stephenson AH, Ellsworth ML, Sprague RS.  Iloprost-and isoproterenol-induced increases in cAMP are regulated by different phosphodiesterases in erythrocytes of both rabbits and humans. Am J Physiol Heart Circ Physiol. 296:H1617-24, 2009 (PMC2685344)

Sprague RS, Hanson MS, Achilleus D, Bowles EA, Stephenson AH, Sridharan M, Adderley S, Procknow J, Ellsworth ML. Rabbit erythrocytes release ATP and dilate skeletal muscle arterioles in the presence of reduced oxygen tension. Pharmacol Rep. Jan-Feb;61(1):183-90, 2009. (PMC2906251)

Ellsworth ML, Ellis CG, Goldman D, Stephenson AH, Dietrich HH, Sprague RS.  Erythrocytes: oxygen sensors and modulators of vascular tone. Physiology (Bethesda). Apr;24:107-16, 2009. (Review) (PMC2725440)

Hanson MS, Ellsworth ML, Achilleus D, Stephenson AH, Bowles EA, Sridharan M, Adderley S, Sprague RS.  Insulin Inhibits Low Oxygen-Induced ATP Release from Human Erythrocytes: Implication for Vascular Control. Microcirculation.16(5): 424-33, 2009. (PMC2906128)

Adderley SP, Sridharan, M., Bowles, EA, Stephenson, AH, Ellsworth, ML, Sprague RS.  Protein Kinases A and C Regulate Receptor-Mediated Increases in cAMP in Rabbit Erythrocytes. Amer. J. Physiol.  (Heart and Circ) 298:H586-93, 2010. (PMC2822589)

Ellis, CG, Goldman, D, Hanson, M, Stephenson, AH, Milkovich, S., Benlamri, A, Ellsworth, ML, Sprague, RS. Defects in Oxygen Supply to Skeletal Muscle in Prediabetic ZDF Rats, Amer. J. Physiol. (Heart and Circ) 298:H1661-H1670, 2010. (PMC2886624)

Hanson, MS, Stephenson, AH, Bowles, EA and Sprague, RS: Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of phosphodiesterase 3 and phosphoinositide 3-kinase.  Exp Biol & Med, 235:256-262, 2010. (PMC2892266)

Adderley, SP, Sprague, RS, Stephenson, AH, and Hanson, MS. Regulation of cAMP by Phosphodiesterases in the Erythrocyte. Pharmacological Reports (Review) 52:475-482, 2010. (PMC2922877)

Sprague, R.S., Goldman, D., Bowles, E.A., Achilleus, D., Stephenson, A.H., Ellis, C.G. and Ellsworth, M.L.: Divergent effects of low O2 tension and iloprost on ATP release from erythrocytes of humans with type-2 diabetes: Implications for O2 supply to skeletal muscle. Amer. J. Physiol. (Heart and Circ) 299:H566-H573, 2010 PMID: 20511412 (PMCID pending)

Sridharan,M,  Sprague, RS, Adderley, SP., Bowles, EA., Ellsworth, ML. and Stephenson, AH.: Diamide decreases deformability of rabbit erythrocytes and attenuates low oxygen tension-induced ATP release. Exp Biol & Med 235:1142-1148, 2010. PMID: 20682601 (PMCID pending)

Sridharan, M., Adderley,SP., Bowles, EA., Egan, TM., Stephenson, AH., Ellsworth, ML. and Sprague, RS.  Pannexin 1 is the conduit for low oxygen tension-induced ATP release from human erythrocytes. Amer. J. Physiol. (Heart and Circ) (in press) [EPub: July 9, 2010] PMID: 20511412 (PMCID pending)

Sprague, RS and Ellsworth, M.L.: Vascular disease in pre-diabetes: New insights derived from systems biology. Missouri Med. (in press July/August 2010)

Sprague, RS, Bowles, EA, Achilleus, D and Ellsworth, ML: Erythrocytes as controllers of perfusion distribution in the microvasculature of skeletal muscle.  Acta Physiol (in press)