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.

Stroke Repair via Biomimicry of the Subventricular Zone

“…There is a bidirectional relationship between cells and ECM proteins, where ECM proteins, once secreted, interact with cells to both induce and maintain the regulatory properties of this barrier system (Baeten and Akassoglou, 2011). These proteins include collagen, fibronectin, laminin, tenascin, and proteoglycans, inter acting closely with ECs, astrocytes, PCs, and microglial, which secrete these proteins poststroke.…”

“…As one example, the inclusion of fibronectin derived Arg-Gly-Asp (RGD) to poly-(ethylene glycol) (PEG) hydrogel systems illustrates improved human MSCs cell survival in vitro (Salinas and Anseth, 2008). Human plasma fibronectin and human plasma fibrinogen demonstrate enhanced survival of cells and increased cell metabolic activity in vitro when encapsulating human MSCs in fibronectin or fibrinogen containing hydrogel capsules, most likely due to integrin clustering and activation of extracellular signaling cascades such as the mitogen activated protein kinase cascade (Karoubi et al, 2009 (Baeten and Akassoglou, 2011). MMP-9, synthesized by both macrophages as well as ECs, is present within and at the periphery of infarct within 24 h, thereby creating a significant disturbance to BBB integrity following stroke.…”

“…Following stroke, OPN is upregulated around the infarct zone, and appears to be beneficial after ischemic insult. In rat pups, OPN injections are correlated with reduction in infarct volume and improvement in functional recovery following ischemia (Baeten and Akassoglou, 2011). Fibrinogen, a major plasma protein involved in blood coagulation, cannot normally penetrate the CNS parenchyma due to the BBB.…”

“…In stroke, however, fibrinogen can occlude blood vessels and leak in the brain, forming deposits and potentially increasing inflammation. In order to remove fibrin to reestablish blood flow, enzymatic degradation by plasmin as well as MMP-2/9 activity is mechanistically helpful (Baeten and Akassoglou, 2011). Considering the alteration of the ECM composition in response to BBB disruption and the direct impact on neurologic disease are functionally important when considering ECM functions in physiology and disease pathology.…”

Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context

“…Mediators of this process include specific adhesion molecules and proteases (e.g., integrins α5, β1, β3, cathepsin-S, matrix metalloproteinases (MMPs), and E-selectin [47,[49][50][51][52][53]). The perivascular niche (PVN) is another critical point of tumour cell attrition-most are unable to tolerate the neuroinflammatory reaction that is rapidly instigated by microglia and astrocytes [28,45,48,[54][55][56][57][58][59][60][61]. Cross-talk with resident pericytes and endothelia in the PVN seems to be key for tumour cell survival, quiescence, and therapeutic resistance-capabilities that underpin dormancy [62].…”