Increased levels of nitric oxide may pathologically affect functional hyperemia in the retina: model and simulation

Abstract

Purpose : The role of nitric oxide (NO) in regulating neurovascular coupling (NVC) in the retina is still poorly understood. Experimental data of flicker light-induced functional hyperemia (FH) in humans (Newman et al (2013)) seem to indicate that increased NO levels mediated by 20- hydroxyeicosatetraeonic acid (20-HETE) reduce vasodilation. In this study we propose a multiphysics/multiscale mathematical model to theoretically investigate the effect of an increased level of neural NO (nNO) on the vasodilation of retinal arterioles.

Methods : Retinal vasculature is described by an equivalent electrical circuit (EEC) of resistive and capacitive compartments. NVC is described by the interaction between vasoactive agents synthesized by active neurons and astrocytes and smooth muscle cell contraction/dilation. Model inputs are blood pressure at the central retinal artery and vein, intraocular pressure, nNO and glutamate (GLU) post-synaptic levels. Kirchhoff current law is solved at each node of the circuit to determine the time evolution of nodal blood pressures and compartment diameters.

Results : Fig. 1 shows the simulated FH in humans for a GLU signal modeling a 20s flicker light stimulus. The y-axis is the % change in mean arterial diameter (MAD). Results indicate that FH is correctly represented only if both large and small arterioles (LA, SA) are assumed to be neurovascularly active (NVA). Fig. 2 shows the simulated effect on vasodilation due to a 60s stimulus of increased nNO level with respect to baseline (nNOb) added to GLU. Results indicate that elevated nNO may reduce vasodilation by a factor of 4.

Conclusions : Model simulations suggest that NVC has a noticeable impact on FH in the retina and that a value of nNO above baseline may significantly reduce vasodilation. These findings suggest that increased NO levels may be responsible for suppressing flicker-evoked vasodilation in diabetic retinopathy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Fig. 1. Effect of NVA compartments on % change in MAD. Black circles: experimental data. Black line: simulation of a single LA. Blue line: simulation of EEC where only LAs are NVA. Red line: simulation of EEC where LAs and SAs are NVA.

 

Fig. 2. Effect of nNO levels on % change in MAD. Black circles: experimental data. Red line: simulation of EEC with nNO = nNOb. Blue line: simulation of EEC with nNO > nNOb.