Brain endothelial gap junction coupling enables rapid vasodilation propagation during neurovascular coupling

Abstract

To meet the brain's moment-to-moment energy demand, neural activation rapidly increases local blood flow. This process, known as neurovascular coupling, involves rapid, coordinated vasodilation of the brain's arterial network. Here, we demonstrate that endothelial gap junction coupling enables long-range propagation of vasodilation signals through the vasculature during neurovascular coupling. The molecular composition of these gap junctions is zonated along the arterio-venous axis, with arteries being the most strongly coupled segment. Using optogenetics and visual stimuli in awake mice, we found that acute, arterial endothelial cell type-specific deletion of Cx37 and Cx40 abolishes arterial gap junction coupling and results in impaired vasodilation. Specifically, we demonstrated that arterial endothelial gap junction coupling determines both the speed and the spatial extent of vasodilation propagation elicited by neural activity. These findings indicate that endothelial gap junctions serve as a signaling highway for neurovascular coupling, enabling flexible and efficient distribution of limited energetic resources.

Keywords: blood flow; brain endothelial cell; cerebrovasculature; connexin; functional hyperemia; gap junction; hemodynamics; in vivo imaging; neurovascular coupling; vasodilation.