COMPUTATIONAL MODELING OF NEUROVASCULAR COUPLING AT THE GLIOVASCULAR UNIT

A growing number of studies indicate the possible involvement of astrocytes in triggering or modulating neurovascular coupling (NVC), i.e. the local dilation of blood vessels in the brain in response to neuronal activity (Lia et al. 2023). Astrocytes possess specialized subcellular compartments, named endfeet, that surround arterioles and capillaries, ideally positioned to mediate NVC. The contribution to NVC of various vasodilators, such as epoxyeicosatrienoic acid (EET), nitric oxyde (NO), or prostaglandin E2 (PGE2) remains poorly understood. Previous computational modeling works have contributed to improving our understanding of the role of astrocytes in NVC, showing for example that EET impacts NVC only when the astrocyte membrane is depolarized (Kenny et al. 2018). In this study, we focus on the PGE2 pathway in astrocytes. We implement an ODE model based on previous work (De Pittà et al. 2019, Barrett et al. 2012), describing PGE2 signaling in astrocytes, a simplified NO pathway in neurons, and arteriole diameter dynamics. Our results provide new insights into the role of astrocyte-mediated PGE2 release in NVC. Using experimental data (Institoris et al. 2022), we show that this pathway could be responsible for the 'late' but not the 'early' response of NVC at the arteriolar level. We further identify distinct contributions of PIP2-derived and phosphatidic acid-derived (calcium-dependent) diacylglycerol on the arteriole diameter. Finally, simulations using a spatialized astrocyte geometry indicate that NVC is more efficient when synaptic stimulation occurs at the endfoot level rather than in other astrocytic compartments.