Pharmacological activation of cGMP signaling promotes astrocyte remodeling and enrichment of perivascular GLUT1 in the murine retina.

Astrocytes regulate metabolic exchange between the vasculature and neurons in the central nervous system (CNS). In the retina of the eye, also a component of the CNS, astrocyte endfeet couple to vascular elements to mediate glucose uptake via the glucose transporter GLUT1 and shuttle metabolic resources to the axons of retinal ganglion cells (RGCs), which provide visual input to the brain. In addition to its own transcriptional regulation, GLUT1 is also modulated by signaling pathways that influence its subcellular localization at the astrocyte-vascular interface. For example, cyclic guanosine monophosphate (cGMP) signaling, a key regulator of vascular tone, is associated with changes in retinal astrocyte morphology and is implicated in age-related loss of RGCs, suggesting a potential role in astrocyte function within the neurovascular unit. Here, we tested this possibility directly by investigating the effects of 8-Br-cGMP on astrocyte morphology, vascular interactions, and GLUT1 localization in the retina. Using a transgenic mouse that allows resolution of individual astrocytes in great detail across the retina (the G-MORF mouse), we show that acute elevation of 8-Br-cGMP increases astrocyte coverage area without altering overall vascular structure. 8-Br-cGMP treatment was also associated with enhanced astrocyte-vascular association, reflected by increased endfoot coverage of blood vessels and altered scaling of astrocyte contact with vessel size. Treatment to increase cGMP signaling promoted redistribution of GLUT1 to astrocyte perivascular endfeet without changing overall levels of GLUT1. Together, these findings indicate that increased cGMP signaling induces coordinated structural and molecular remodeling of astrocytes at the vascular interface. These results provide important insight into how cyclic nucleotide signaling pathways may regulate astrocyte organization in the retina and suggests a potential role for cGMP in modulating astrocyte-vascular interactions within the neurovascular unit.