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. 2024 Jul 4;15:1394725. doi: 10.3389/fphys.2024.1394725

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Copyright © 2024 O’Hare, Millican and Ebong.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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In healthy conditions, the GCX plays an essential role in facilitating proper NO production: (1.) The GCX acts a mechanosensor upon shear stress exposure, facilitating a variety of essential cellular responses. (2.) Such responses include the opening of calcium ion channels, which increases calcium ion availability within the cell and PI3K pathway initiation, leading to eNOS phosphorylation. (3.) Calcium ions form a complex with calmodulin and phosphorylated eNOS, converting inactive eNOS into its active form. (4.) Active eNOS catalytically converts L-arginine into NO and L-citruline. (5.) NO release relaxes smooth muscle cells, leading to blood vessel dilation. (6.) Proper dilation allows for proper blood supply of nutrients to the brain and waste clearance out of it, effectively coupling the two systems (Tarbell and Pahakis, 2006; Dudzinski and Michel, 2007; Kumagai et al., 2009). Created with BioRender.com.