Cell adhesion and signaling networks in brain neurovascular units

Abstract

Purpose of review: Central nervous system (CNS) neurovascular units are multicellular complexes consisting of neurons and astrocytes, vascular endothelial cells and pericytes, as well as an assortment of growth factors and extracellular matrix (ECM) proteins. Here, I will discuss the current knowledge of signaling networks essential for the development and physiology of CNS neurovascular units, particularly in the brain.

Recent findings: Molecular genetic studies have identified various signaling proteins that regulate the formation and function of CNS neurovascular units. These include members of the integrin family of ECM adhesion receptors, ECM proteins such as Wnts and latent transforming growth factor betas, and various transcriptional regulators, including beta-catenin and the inhibitors of DNA binding (Ids).

Summary: Neurovascular units are the cellular and molecular interfaces between the circulatory system and the CNS. Recent molecular genetic analyses in mice and other model organisms have revealed the first mechanisms underlying bidirectional communication between neural and vascular components. In particular, ECM-mediated adhesion and signaling pathways have been identified as essential for neurovascular development and physiology. Understanding how these various gene products normally control neurovascular unit formation and function will lend new insights into the causes and possible treatments of debilitating neurovascular-related diseases such as birth defects, stroke, and age-related dementia.

Figure 1. A summary of adhesion and signaling pathways in neurovascular units

(a) The multicellular composition of a central nervous system (CNS) neurovascular unit composed of vascular endothelial cells and pericytes, neurons, and glia. Extracellular matrix (ECM)-rich basement membranes separate the various neural and vascular cell types. (b) A more detailed view of the boxed area in (a) showing a vascular endothelial cell and perivascular glial cell separated by a vascular basement membrane. The αvβ8 integrin–transforming growth factor (TGF)β adhesion and signaling axis is essential for proper linkage between perivascular glial cells and vascular endothelial cells within neurovascular units. Paracrine TGFβ signaling events in endothelial cells likely involve the SMADs. In perivascular cells, αvβ8 integrin interacts with the Band 4.1s, which may link this integrin with multiple intracellular signaling effectors, including β-Pix. Wnt7a and Wnt7b are ECM-associated proteins expressed by neural cells of the CNS parenchyma that regulate the development of the neurovascular unit. Wnt-mediated signaling pathways require β-catenin in vascular endothelial cells. BBB, blood–brain barrier.