1. Hasan Al-Taee Medical Biophysics Department Western University Wednesday April 4 th, 2012 A NEW MODEL FOR O 2 DEPENDENT ATP SIGNALING BETWEEN ERYTHROCYTES AND CAPILLARY ENDOTHELIUM

2. INTRODUCTION At the microvascular level, O 2 supply needs to be matched to O 2 demand. Evidence that red blood cells (RBCs) release ATP when there is a decrease in O 2 saturation (Bergfeld & Forrester, 1992; Jagger et al, 2001) Evidence that ATP applied to venules, capillaries or arterioles causes ascending vasodilation and increased vascular blood flow (Ellsworth et al, 2009)

3. MOTIVATION Existing model of microvascular flow regulation based on O 2 dependent release of ATP by RBCs (Arciero et al, 2008) Implied: Capillaries not main site of RBC ATP-based flow regulation, despite being main site of blood-tissue O 2 delivery Hematocrit- not RBC velocity or supply rate- is key factor in ATP signaling to endothelium by RBCs

4. OBJECTIVES Develop new model of O 2 dependent ATP release in capillaries Determine if new model Increases ATP-based O 2 supply regulation in capillaries Allows RBC velocity and supply rate to regulate flow at microvascular level

5. HYPOTHESES New model will demonstrate increased importance of RBC ATP release in capillaries when O 2 saturation decreases New model will allow hematocrit, RBC velocity and RBC supply rate to regulate microvascular flow

6. METHODS Solve for ATP concentration in a single capillary One-dimensional steady state convection/reaction equation Change ATP release rate to function of rate of change of saturation with time: dS/dt=Vrbc*dS/dx Change control volume to plasma layer between RBC and vessel wall Plot analytical solutions using Matlab for varying conditions

7. EQUATIONS Arciero equation for ATP concentration C(x): New model for C(x):

8. VARIABLES  0 set to match asymptotic C in Arciero model for S=1 and dS/dx=0  1 set to match mean C(x) in Arciero model for baseline capillary conditions

9. PARAMETERS R 0 = 1.4x10 -9 mol s -1 cm -3 R 1 = 0.891 δ = 1 μm (plasma layer) D= 6x10 -4 cm (diameter) H T =0.20xH f (hematocrit) V rbc =0.025xV f (RBC velocity, cm/s) M 0 =1.5x10 -4 xM f (O 2 consumption rate, ml O 2 ml -1 s -1 ) ρ 0 =1.53x10 -10 mol s -1 cm -3 ρ 1 =8.0x10 -9 mol cm -3

10. RESULTS Baseline case

11. Increased oxygen consumption, baseline blood flow

12. Increased oxygen consumption, increased velocity

13. Increased oxygen consumption, increased velocity and hematocrit

14. DISCUSSION A decrease in oxygen saturation in capillaries will cause an increase in ATP release rate by RBCs This causes conducted signal along the capillary that will produce dilation of upstream arterioles and increased blood flow Larger decrease in saturation results in greater ATP release in capillaries in the new model, but not in Arciero model New model can maintain increase in hematocrit, velocity, and product (supply rate) via increased ATP, but Arciero model can only maintain smaller hematocrit increase

15. CONCLUSION New model, if correct, implies capillaries could be main site of RBC ATP-based flow regulation and that hematocrit and RBC velocity can both be regulated via oxygen-dependent release of ATP by RBCs

16. ACKNOWLEDGMENTS Dr. Daniel Goldman Teaching Assistants

17. QUESTIONS ?