A new model for o 2 dependent ATP signaling between erythrocytes and capillary endothelium

1. A new model for o2 dependent ATP signaling between erythrocytes and capillary endothelium Hasan Al-Taee Medical Biophysics Department Western University Wednesday April 4th, 2012

2. Introduction • At the microvascular level, O2 supply needs to be matched to O2 demand. • Evidence that red blood cells (RBCs) release ATP when there is a decrease in O2 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 O2 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 O2 delivery • Hematocrit- not RBC velocity or supply rate- is key factor in ATP signaling to endothelium by RBCs

4. Objectives • Develop new model of O2 dependent ATP release in capillaries • Determine if new model • Increases ATP-based O2 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 O2 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 • ρ0 set to match asymptotic C in Arciero model for S=1 and dS/dx=0 • ρ1 set to match mean C(x) in Arciero model for baseline capillary conditions

9. Parameters • R0 = 1.4x10-9 mol s-1 cm-3 • R1= 0.891 • δ = 1 μm (plasma layer) • D= 6x10-4 cm (diameter) • HT=0.20xHf (hematocrit) • Vrbc=0.025xVf (RBC velocity, cm/s) • M0=1.5x10-4xMf (O2 consumption rate, ml O2 ml-1 s-1) • ρ0=1.53x10-10 mol s-1 cm-3 • ρ1=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 ?