Perlecan and the Blood-Brain Barrier: Beneficial Proteolysis?

Abstract

The cerebral microvasculature is important for maintaining brain homeostasis. This is achieved via the blood-brain barrier (BBB), composed of endothelial cells with specialized tight junctions, astrocytes, and a basement membrane (BM). Prominent components of the BM extracellular matrix (ECM) include fibronectin, laminin, collagen IV, and perlecan, all of which regulate cellular processes via signal transduction through various cell membrane bound ECM receptors. Expression and proteolysis of these ECM components can be rapidly altered during pathological states of the central nervous system. In particular, proteolysis of perlecan, a heparan sulfate proteoglycan, occurs within hours following ischemia induced by experimental stroke. Proteolysis of ECM components following stroke results in the degradation of the BM and further disruption of the BBB. While it is clear that such proteolysis has negative consequences for the BBB, we propose that it also may lead to generation of ECM protein fragments, including the C-terminal domain V (DV) of perlecan, that potentially have a positive influence on other aspects of CNS health. Indeed, perlecan DV has been shown to be persistently generated after stroke and beneficial as a neuroprotective molecule and promoter of post-stroke brain repair. This mini-review will discuss beneficial roles of perlecan protein fragment generation within the brain during stroke.

Border patrol: Insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders

“…This occurs without changes in permeability of the blood-brain barrier, suggesting the tissue barrier function of the perlecan core protein lies in modules N-terminal to domain V, likely in domains II-IV that also are present in invertebrates with distinct body compartments but lacking domain I. Consistent with this notion, further degradation of perlecan in endothelial basement membranes leads to compromise of the blood-brain barrier (Kahle et al, 2012; Roberts et al, 2012). During arterial injury, perlecan turnover again plays a role in tissue recovery.…”

“…To do this, they express both glycosidases and proteases (Heppner et al, 1996; Walch and Marchetti, 1999; Whitelock et al, 1996) that allow them to degrade the core protein and the associated HS chains. For metastases to brain, the perlecan layer that serves as part of the blood-brain barrier in the vascular basement membrane must be breached (Roberts et al, 2012). Likewise, drugs and nanodelivery systems designed to reach the brain must be made to consider the properties of the perlecan barrier surrounding the tight endothelium in the brain.…”

Some cross-talks between immune cells and epilepsy should not be forgotten

“…Peripheral immune system consists of immune organs, immune cells and immune molecules, among which peripheral blood cells (PBCs) are the main executors during immune response. Under the physiological condition, an intact BBB, which is composed of tight junction between endotheliocytes (ECs), ECs, synapse of glial cell, and basal lamina, serves as a physical and chemical barrier dividing the central nervous system (CNS) from peripheral blood [4]. After epileptic seizure, the integrality and function of blood brain barrier (BBB) are interrupted by multiple factors, leading to massive signaling transmissions and substance exchanges between the brain parenchyma and peripheral blood, such as extravasation of white blood cells [5] into the brain and S-100 [6] into the peripheral blood.…”

Real‐time acquisition of transendothelial electrical resistance in an all‐human, in vitro , 3‐dimensional, blood‐brain barrier model exemplifies tight‐junction integrity

“…Perlecan also appears to have a critical role in basement membrane maintenance and stability (20, 21). Perlecan is most abundant in the CNS capillary BL, interacting with other components of the BL and several growth factors, suggesting it has a role in the formation and stabilization of the BL (20, 22). Deguchi et al (23) suggested that perlecan has an important role in BBB function via growth factor regulation, such as fibroblast growth factor, a soluble factor that is likely essential for maintaining BBB integrity.…”