A theoretical investigation of the role of arachidonic acid in astrocyte vasoactive agent production

Abstract

Purpose :
Astrocytes are glial cells that produce vasoactive agents triggering smooth muscle cell dilation and contraction. Fig. 1 represents the pathway transducing input stimuli of glutamate (Glu) and neuronal nitric oxide (nNO) into the synthesis of two arachidonic acid (AA) metabolites, epoxyeicosatrienoic (EET) and 20-hydroxyeicosatetraeonic (20-HETE) acids. Abnormal changes in AA level have been associated with disease conditions, such as glaucoma and migraines, and this may lead to dysregulation of EET and 20-HETE production. In this work, we propose a mathematical model to theoretically investigate the relationship between AA, EET and 20-HETE.

Methods :
Astrocyte function is modeled by an ordinary differential/algebraic equation system describing: (1) chemical balance of unbuffered calcium (Ca) and inositol 3-phosphate inside the cytosol; (2) Ca-mediated synthesis of AA; and (3) AA-mediated production of 20-HETE and EET. Simulations are conducted to study the temporal evolution of 20-HETE and EET as a function of the parameter AA_max representing the maximum increase in AA concentration above baseline.

Results :
Fig. 2 shows simulated 20-HETE and EET as a result of a square pulse of Glu (top panel, left) and a constant nNO equal to baseline value (top panel, right). Bottom panel curves are obtained with 5 values of AA_max, from 0 to 58 μM, with 28μM corresponding to physiological conditions. Results show that increasing AA_max improves vasoactive agent production. Denoting by ρ the ratio between the maximum EET and 20-HETE concentrations for each value of AA_max, we see that ρ increases from 3.75 to 5.5, with a value of 4.6 in physiological conditions.

Conclusions :
The proposed mathematical model allowed us to simulate vasoactive agent production by an astrocyte under Glu and nNO input stimuli. Model predictions suggest that impaired AA synthesis affects more significantly EET than 20-HETE production. This may advance the understanding of pathogenic conditions associated with AA dysregulation, including blood flow and intraocular pressure dysregulation.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Fig. 1. Glu and nNO are inputs to the astrocyte which synthesizes EET (vasodilator) and 20-HETE (vasoconstrictor). AA contributes to mediate this synthesis.

 

Fig. 2. Top: Glu stimulus (left panel); nNO stimulus (right panel). Dashed black lines represent baseline values. Bottom: 20-HETE (left panel) and EET (right panel) as a function of AA_max.