Partial recovery of the damaged rat blood–brain barrier is mediated by adherens junction complexes, extracellular matrix remodeling and macrophage infiltration following focal astrocyte loss

Abstract

Blood-brain barrier (BBB) dysfunction is a feature of many neurodegenerative disorders. The mechanisms and interactions between astrocytes, extracellular matrix and vascular endothelial cells in regulating the mature BBB are poorly understood. We have previously shown that transitory GFAP-astrocyte loss, induced by systemic administration of 3-chloropropanediol, leads to reversible disruption of tight junction complexes and BBB integrity to a range of markers. However, early restoration of BBB integrity to dextran (10-70 kDa) and fibrinogen was seen in the absence of paracellular tight junction proteins claudin-5 and occludin. In the present study we show that in the GFAP-astrocyte lesioned rat inferior colliculus, paracellular expression of adherens junction proteins (VE-cadherin and β-catenin) was maintained in vascular endothelial cells that lacked paracellular claudin-5 expression and which showed reversible post-translational occludin modification. Claudin-1 expression paralleled the loss and recovery of claudin-5, while claudin -3 or -12 immunoreactivity was not detected. In addition, the extracellular matrix, as visualized by laminin and fibronectin, underwent extensive reversible remodeling and perivascular CD169 macrophages become abundant throughout the lesioned inferior colliculus. At a time that GFAP-astrocytes repopulated the lesion area and tight junction proteins were returned to paracellular domains, the extracellular matrix and leukocyte profiles normalized and resembled profiles seen in control tissue. This study supports the hypothesis that a combination of paracellular adherens junctional proteins, remodeled basement membrane and the presence perivascular leukocytes provide a temporary barrier to limit extravasation of macromolecules and potentially neurotoxic substances into the brain parenchyma until tight junction proteins are restored to paracellular domains.

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

“…This major TJ protein that plays an important role in TJ integrity has a low expression in cerebrovascular endothelium. In agreement with other studies,30, 31 protein expression of CLDN1 in the intact control (NC) HBMECs was extremely low and almost undetectable either with immunofluorescence staining or Western blot. Similar to NC samples, in the OGD cells transfected with control oligonucleotides (CLDN1 distribution and expression was similar in OGD/IC and OGD/MC control samples), CLDN1 distribution was mostly cytoplasmic and the expression was weak (Figure 5A, OGD/IC panel).…”

“…While CLDN5 is highly expressed in the brain endothelium, CLDN1 expression in cerebral capillaries is low and was only confirmed to be present in human, rat, and sheep BBB 3, 30, 31. Regardless of the low expression, CLDN1 function in human brain capillaries is critical for the maintenance of the BBB integrity during neuroinflammation and brain tumor 29, 44.…”

Ischemic–hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus

“…Damage to astrocytes, cells that contribute to the integrity of the blood-brain barrier, has been associated with a remarkable alteration in the structure of the blood vessel wall [40][41][42]. In the case of pilocarpinetreated rats, we described the presence of microhemorrhages or extravasated erythrocytes around the vessels in CA3 [17] which are neuropathological findings reminiscent of those observed in strokeprone spontaneously hypertensive rats when they developed elevated blood pressure levels [43].…”

Fibronectin changes in eosinophilic meningitis with blood–CSF barrier disruption

“…In addition to adherens junctions, ECM remodeling with increased fibronectin expression under pathological conditions is vital in restoring partial BBB integrity (Willis et al, 2013). The high molecular weight of fibronectin and its strong adhesion to cellular and connective tissue surfaces strongly inhibit the filtration of plasma fibronectin through an intact BBB (Weller et al, 1990).…”