Varying perivascular astroglial endfoot dimensions along the vascular tree maintain perivascular-interstitial flux through the cortical mantle

Abstract

The glymphatic system is a recently defined brain-wide network of perivascular spaces along which cerebrospinal fluid (CSF) and interstitial solutes exchange. Astrocyte endfeet encircling the perivascular space form a physical barrier in between these two compartments, and fluid and solutes that are not taken up by astrocytes move out of the perivascular space through the junctions in between astrocyte endfeet. However, little is known about the anatomical structure and the physiological roles of the astrocyte endfeet in regulating the local perivascular exchange. Here, visualizing astrocyte endfoot-endfoot junctions with immunofluorescent labeling against the protein megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1), we characterized endfoot dimensions along the mouse cerebrovascular tree. We observed marked heterogeneity in endfoot dimensions along vessels of different sizes, and of different types. Specifically, endfoot size was positively correlated with the vessel diameters, with large vessel segments surrounded by large endfeet and small vessel segments surrounded by small endfeet. This association was most pronounced along arterial, rather than venous segments. Computational modeling simulating vascular trees with uniform or varying endfeet dimensions demonstrates that varying endfoot dimensions maintain near constant perivascular-interstitial flux despite correspondingly declining perivascular pressures along the cerebrovascular tree through the cortical depth. These results describe a novel anatomical feature of perivascular astroglial endfeet and suggest that endfoot heterogeneity may be an evolutionary adaptation to maintain perivascular CSF-interstitial fluid exchange through deep brain structures.

A network model of glymphatic flow under different experimentally-motivated parametric scenarios

“…2A-B; see Methods and C in SM). Note that prior studies ( 23, 28,36 ) suggest CSF from penetrating PVSs primarily enters the ECS via gaps between astrocyte endfeet. The upper and lower bounds that we set on the parenchymal permeability κ par come from two commonly cited studies ( 31,37 ); multiple other studies ( 38–42 ) have reported κ par values within these bounds.…”

“…CSF leaves the perivascular space (green) surrounding penetrating arterioles (red) via gaps of width g and thickness T . The gaps between endfeet are long and narrow, as described by Wang et al ( 28 ). To estimate the hydraulic resistance of the gaps, we consider flow between infinite parallel plates.…”

“…3Q-R, U-V), suggesting the astrocyte endfeet play a critical role. Indeed, a recent study ( 28 ) reported heterogeneity in the size of astrocyte endfeet, with larger endfeet (fewer gaps) surrounding larger vessels, which provides a mechanism that improves the uniformity of cortical perfusion. We intend to implement this feature in future simulations.…”

“…In order to improve on prior idealizations of the glymphatic pathway ( 24, 28 ), we have developed a model of CSF flow in the murine brain based on measurements of the vascular connectivity performed by Blinder et al ( 29,30 ). We use the connectivity between different vessels in this model (Fig.…”

Perivascular pumping of cerebrospinal fluid in the brain with a valve mechanism

“…Indeed, Bork et al [14] recently proposed a mechanical model of flexible endfeet in which a fluctuating pressure causes the endfeet to flap in a way that promotes a directional flow, similar to the action of a bicuspid valve. Several studies using extracellular tracers indicate that fluid communication between PVSs and the ECS occurs mostly through the gaps between endfeet (see the reviews [1,15,16]). (It has also been suggested that some communication occurs through the astrocyte bodies themselves [17].)…”