The importance of laminin at the blood-brain barrier

Abstract

The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components. The mechanistic basis of this barrier is found at multiple levels, including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes, microglia, and astrocyte endfeet. In addition, extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity, not only by providing an adhesive substrate for blood-brain barrier cells to adhere to, but also by providing guidance cues that strongly influence vascular cell behavior. The extracellular matrix protein laminin is one of the most abundant components of the basement membrane, and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior. In this review, we describe the basic structure of laminin and its receptors, the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states, and most importantly, how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity. Finally, we discuss some of the important unanswered questions in the field and provide a "to-do" list of some of the critical outstanding experiments.

Keywords: astrocytes; basement membrane; blood vessels; blood-brain barrier integrity; dystroglycan; endothelial cells; inflammation; integrins; laminin; pericytes.

Figure 1

Schematic representation of the BBB. Endothelial cells (pink) form the innermost layer of blood vessels and are strongly attached to the vascular basement membrane, which is a composite of different ECM proteins (violet), including laminin. Pericytes (red) and their processes closely attach to blood vessels and their cell bodies are located within the vascular basement membrane. Astrocytes within the CNS parenchyma (brown) extend endfeet which also cover the vascular basement membrane, thereby connecting blood vessels to neurons within the brain parenchyma. Microglial cells (green) are highly active motile cells that also form close connections with astrocytes and blood vessels. BBB: Blood-brain barrier; CNS: central nervous system; ECM: extracellular matrix. Created with BioRender.com.

Figure 2

The molecular structure of laminin. Laminin molecules organize as heterotrimers consisting of α (green), β (peach) and γ (orange) subunits of which five α, four β, and three γ have been identified to date. Laminins are named according to their subunit composition; for instance, laminin-111 contains the subunits α1, β1 and γ1. Created with BioRender.com.

Figure 3

Schematic diagram of interactions between laminin and its receptors. Cells of the BBB bind to laminins in the vascular basement membrane via their cognate cell surface receptors, integrins and dystroglycan, which are transmembrane proteins. These receptors form both a transmembrane link between extracellular laminin and the actin cytoskeleton and also promote intracellular signaling events. The cytoplasmic domain of integrins bind to the cytoplasmic adaptor proteins talin, vinculin and α-actinin to form the transmembrane link and bind to several cytoplasmic signaling proteins including FAK and ILK to promote downstream intracellular signaling. The transmembrane β subunit of dystroglycan binds directly to the cytoplasmic adaptor protein dystrophin and thereby links to the actin cytoskeleton. BBB: Blood-brain barrier; FAK: focal adhesion kinase; ILK: integrin-linked kinase. Created with BioRender.com.