Roles of blood-brain barrier integrins and extracellular matrix in stroke

Abstract

Ischemicstroke is a leading cause of death and disability in the United States, but recent advances in treatments [i.e., endovascular thrombectomy and tissue plasminogen activator (t-PA)] that target the stroke-causing blood clot, while improving overall stroke mortality rates, have had much less of an impact on overall stroke morbidity. This may in part be attributed to the lack of therapeutics targeting reperfusion-induced injury after the blood clot has been removed, which, if left unchecked, can expand injury from its core into the surrounding at risk tissue (penumbra). This occurs in two phases of increased permeability of the blood-brain barrier, a physical barrier that under physiologic conditions regulates brain influx and efflux of substances and consists of tight junction forming endothelial cells (and transporter proteins), astrocytes, pericytes, extracellular matrix, and their integrin cellular receptors. During, embryonic development, maturity, and following stroke reperfusion, cerebral vasculature undergoes significant changes including changes in expression of integrins and degradation of surrounding extracellular matrix. Integrins, heterodimers with α and β subunits, and their extracellular matrix ligands, a collection of proteoglycans, glycoproteins, and collagens, have been modestly studied in the context of stroke compared with other diseases (e.g., cancer). In this review, we describe the effect that various integrins and extracellular matrix components have in embryonic brain development, and how this changes in both maturity and in the poststroke environment. Particular focus will be on how these changes in integrins and the extracellular matrix affect blood-brain barrier components and their potential as diagnostic and therapeutic targets for ischemic stroke.

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice

“…Along this line, our dataset shows an induction of SAMHD1 in the postacute phase suggesting a potential role for SAMHD1 in poststroke vascular repair and regeneration. However, several genes are unresolved 7 days after tMCAO especially cell-adhesion molecules such as integrins ITGB2 and ITGA5 as reported previously to be dysregulated in the acute phase (Edwards and Bix, 2018). Previous studies support the therapeutic significance of this group for integrin-based therapeutics (Ley et al, 2016).…”

“…In parallel, lack of oxygen causes a failure of the respiratory chain and mitochondrial function so that pH is reduced and free radicals expand the local tissue damage (Lipton, 1999). Subsequently, a sterile inflammatory reaction going along with a hyperacute imbalance of matrix metallopeptidases (MMPs), especially MMP-9, and their endogenous counterplayers, tissue inhibitor of metallopeptidases (TIMP)-1 and -2 (Barr et al, 2010;Lenglet et al, 2014) triggers the destruction of the crucial endothelial-ECM interface of the BBB (Edwards and Bix, 2018). On the other hand, a step-wise degradation of endothelial cells in the oxygen-deprived area has been observed in the context of permanent and reperfused stroke even without disintegration of tight junction molecules (Krueger et al, 2015).…”

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

“…By interacting with different cell types via integrins and other receptors, the BM contributes to the structural and functional integrity of the neurovascular unit [9,10]. It has been reported that integrin expression is substantially altered after stroke and integrins play an important role in stroke pathogenesis [9,[11][12][13]. Compared to integrins, the BM is relatively understudied.…”

Relationship Between Integrin β1 (ITGB1), β3 (ITGB3) and Intracerebral Hemorrhage (ICH)

“…19,20 In particular, ECM-derived signals are transported to the cytoplasm through integrins that directly 62 recognize components of the ECM, resulting in cytological alterations. 6,11 Therefore, the stimulation of ECM protein-derived signals by integrins makes it possible to accurately regulate the speci city of cells.…”