Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke

Abstract

The blood-brain barrier (BBB) is formed primarily to protect the brain microenvironment from the influx of plasma components, which may disturb neuronal functions. The BBB is a functional unit that consists mainly of specialized endothelial cells (ECs) lining the cerebral blood vessels, astrocytes, and pericytes. The BBB is a dynamic structure that is altered in neurologic diseases, such as stroke. ECs and astrocytes secrete extracellular matrix (ECM) proteins to generate and maintain the basement membranes (BMs). ECM receptors, such as integrins and dystroglycan, are also expressed at the brain microvasculature and mediate the connections between cellular and matrix components in physiology and disease. ECM proteins and receptors elicit diverse molecular signals that allow cell adaptation to environmental changes and regulate growth and cell motility. The composition of the ECM is altered upon BBB disruption and directly affects the progression of neurologic disease. The purpose of this review is to discuss the dynamic changes of ECM composition and integrin receptor expression that control BBB functions in physiology and pathology.

Figure 1

Schematic representation of the BBB before and after ischemia. Healthy microvessels in the brain consist of specialized ECs with TJs, their surrounding endothelial BM (blue) and astrocytic (parenchymal) BM (purple) composed of ECM proteins, and an astrocytic endfeet coverage. Cellular and matrix components of the BBB are connected through a variety of matrix receptors. Pericytes are found within the endothelial BM and occasionally the astrocytic endfeet coverage is interrupted to allow contact of microglia and neurons with the BM. After stroke/ischemia the specialized endothelial characteristics disappear, TJs are lost, fenestrations appear. The BMs become thinner and there is a marked reduction in matrix proteins and receptors. The astrocytic endfeet swell up and the contact with the vessels is lost. There is leakage of fluid, proteins and cells from the vessel lumen. Microglia become activated and might extend processes toward the blood vessels, while pericytes move away. White blood cells transmigrate via an integrin-dependent process across the endothelial BM and via an MMP-dependent process across the parenchymal BM.

Figure 2

Fibrin during thrombus formation and secondary damage in stroke. In stroke, a fibrin clot or fibrin-stabilized thrombus occludes a vessel, stopping blood flow and causing ischemia. The fibrin clot is cleared enzymatically by fibrinolysis or by extravasation in the CNS. Ischemia–reperfusion is followed by inflammation and disruption of the BBB. Deposition of fibrin into the CNS parenchyma results in microglia activation via CD11b/CD18, leading to increased inflammation; astrocyte activation via TGF-β, resulting in neurocan deposition; and inhibition of neurite outgrowth through αvβ3 and EGF receptor. Fibrinogen-induced proinflammatory and neurodegenerative changes in the CNS may exacerbate damage after stroke.