Integrin-mediated regulation of neurovascular development, physiology and disease

Abstract

The mammalian central nervous system (CNS) is comprised of billions of neurons and glia that are intertwined with an elaborate network of blood vessels. These various neural and vascular cell types actively converse with one another to form integrated, multifunctional complexes, termed neurovascular units. Cell-cell communication within neurovascular units promotes normal CNS development and homeostasis, and abnormal regulation of these events leads to a variety of debilitating CNS diseases. This review will summarize (1) cellular and molecular mechanisms that regulate physiological assembly and maintenance of neurovascular units; and (2) signaling events that induce pathological alterations in neurovascular unit formation and function. An emphasis will be placed on neural-vascular cell adhesion events mediated by integrins and their extracellular matrix (ECM) ligands. I will highlight the role of a specific adhesion and signaling axis involving alphavbeta8 integrin, latent transforming growth factor beta's (TGFbeta's), and canonical TGFbeta receptors. Possible functional links between components of this axis and other signal transduction cascades implicated in neurovascular development and disease will be discussed. Comprehensively understanding the pathways that regulate bidirectional neural-vascular cell contact and communication will provide new insights into the mechanisms of neurovascular unit development, physiology and disease.

Figure 1

A Model of αvβ8 integrin-mediated adhesion and signaling pathways in neurovascular units. (A) The multicellular composition of a central nervous system neurovascular unit, comprised of a capillary endothelial cell and pericyte, as well as neurons and astrocytes that adhere to extracellular matrix proteins within intervening vascular basement membranes. (B) A more detailed view of the boxed area in (A) showing the astrocyte-endothelial cell interface that is coupled, in part, by the αvβ8 integrin-TGFβ adhesion and signaling axis. αvβ8 integrin on the astrocyte binds to latent TGFβ's in the vascular basement membrane and induces TGFβ activation, resulting in liberation of TGFβ from the extracellular matrix. TGFβ signaling pathways in endothelial cells are likely regulated by canonical TGFβ receptors, but may also involve cross talk with Neuropilin 1. In astrocytes, αvβ8 integrin also interacts with Band 4.1B, a cytoskeletal adaptor protein, which may link this integrin with other intracellular and cell surface signaling effectors. Various molecular genetic data reveal that perturbation of normal astrocyte-endothelial cell coupling, via ablation of genes encoding the αvβ8 integrin or TGFβ signaling components, leads to abnormal neurovascular development and premature death.