The vascular basement membrane in the healthy and pathological brain

Abstract

The vascular basement membrane contributes to the integrity of the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). The BCECs receive support from pericytes embedded in the vascular basement membrane and from astrocyte endfeet. The vascular basement membrane forms a three-dimensional protein network predominantly composed of laminin, collagen IV, nidogen, and heparan sulfate proteoglycans that mutually support interactions between BCECs, pericytes, and astrocytes. Major changes in the molecular composition of the vascular basement membrane are observed in acute and chronic neuropathological settings. In the present review, we cover the significance of the vascular basement membrane in the healthy and pathological brain. In stroke, loss of BBB integrity is accompanied by upregulation of proteolytic enzymes and degradation of vascular basement membrane proteins. There is yet no causal relationship between expression or activity of matrix proteases and the degradation of vascular matrix proteins in vivo. In Alzheimer's disease, changes in the vascular basement membrane include accumulation of Aβ, composite changes, and thickening. The physical properties of the vascular basement membrane carry the potential of obstructing drug delivery to the brain, e.g. thickening of the basement membrane can affect drug delivery to the brain, especially the delivery of nanoparticles.

Keywords: Alzheimer’s disease; blood-brain barrier; drug delivery; stroke; the brain’s vascular basement membrane.

Figure 1.

Illustration showing the architecture of the vascular basement membrane. The basement membrane is composed of different extracellular matrix (ECM) proteins, with the majorities being collagen IV, various laminin isoforms, perlecan, and nidogen-1. Laminin and collagen IV can self-assemble into 3D networks that are interconnected by nidogen and perlecan. Adopted from Hallmann et al.

Figure 2.

The differential expression of laminins along the cerebrovascular tree. The illustration shows the lining of the parenchymal (light blue) and endothelial basement membrane (dark blue) along the cerebrovascular tree with a cross section of the pial vessel, penetrating arteriole, capillary, and postcapillary venule. Laminin α1 and α2 are expressed by pial cells of the pia mater (yellow line) and astrocytes, respectively, and these can be found in the parenchymal basement membrane of the penetrating arterioles. As the contribution from the pial cells diminishes, the parenchymal basement membrane of the capillaries and postcapillary venules no longer has laminin α1. Laminin α4 is uniformly expressed in the endothelial basement membrane along the cerebrovascular tree. Oppositely, laminin α5 is expressed in the endothelial basement membrane of the pial vessel, penetrating arterioles, and capillaries but has patchy distribution along the postcapillary venules. In capillaries, there is no clear separation of the endothelial and parenchymal basement membranes, and the basement membrane thus appears as a single entity that envelops the pericyte. In postcapillary venules, the parenchymal and endothelial basement membranes line the border of the virtual perivascular space (PVS). E: Endothelial cells, P: pericytes, A: Astrocyte endfeet.

Figure 3.

Schematic illustration of the vascular basement membrane at the blood-brain barrier (BBB) in health, stroke, and Alzheimer’s disease (AD). Normally the vascular basement membrane is well organized. In stroke, the basement membrane (continued) Figure 3. continued. proteins are degraded by mechanisms that may involve different protease-systems, e.g. matrix metalloproteinases (MMPs) such as MMP-2 and -9, urokinases of the plasminogen activator system, and the cysteine proteases cathepsin B and L. Stroke is also accompanied by decreased BBB integrity with leakage of serum proteins, increased production of inflammatory cytokines and reactive oxygen species, and invasion of inflammatory cells. Oppositely, in AD, accumulation of amyloid beta (Aβ) as cerebral amyloid angiopathy (CAA) in the basement membrane of both larger vessels and capillaries is observed. Furthermore, basement membrane thickening and changes in the protein composition of the basement membrane with increased deposition of, e.g., perlecan can also be seen in AD. BM: Basement membrane.

Figure 4.

Images showing the restrictive capabilities of the basement membrane and its thickening in Alzheimer’s disease. (a, b) The images illustrate the distribution of the iron particles Feridex along the basement membrane, after experimental opening of the blood-brain barrier using mannitol. The images are adapted from Muldoon et al. Permission American Society for Neuroradiology. L: Lumen, EC: endothelial cell, BM: basement membrane, MA: myelinated axon. (c, d) Images of capillaries from a patient with AD in a region with only few amyloid plaques (c) and a region severely affected by plaques (d). The arrowheads outline the basement membrane as a thin line in the region with only few plaques and in the regions severely affected by plaques the basement membrane have regional thickenings. The images are adapted from Perlmutter. L: Lumen, e: endothelial cell. Permission Springer Nature.