Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

Abstract

Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the "neurovascular unit," is the brain's multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.

Keywords: blood-brain barrier; endothelial cells; endothelial glycocalyx; ischemic stroke; mechanotransduction; neuroprotection; neurovascular unit.

Figure 1

Structure of the neurovascular unit (NVU). Endothelial cells (ECs) form the inner most layer of the NVU and are connected to each other via tight junctions (TJs). Surrounding the ECs are pericytes in the case of capillaries or smooth muscle cells in the case of larger cerebrovasculature such as veins and arteries. Additionally, astrocytes and neurons of the NVU extend foot-processes or axons, respectively, that also help regulate NVU function. Finally, microglia, which are the brain’s resident immune cells, also contribute to NVU regulation. Collectively, ECs and these supportive cells help maintain the proper function of the blood-brain barrier (BBB). This figure is reprinted from Abbott et al. (2010)) “Structure and function of the blood-brain barrier,” Neurobiology of Disease, 37 (1): 12–25, with permission from Elsevier.

Figure 2

Structure of brain EC-cell junctions. EC-to-EC junctions consist of permeability regulating protein complexes in both tight and adherens junctions (AJs). TJs, which are more strongly associated with permeability regulation, consist of the occludin, junctional adhesion molecule, and claudin families of proteins linked to the cytoskeleton via zona occludens (ZO) proteins. AJs, which also play a role in permeability regulation, are composed of vascular endothelial (VE)-cadherin dimers similarly linked to the cytoskeleton via an array of linker proteins, such as catenin. In addition to these major junctional components, EC junctions also contain numerous supporting proteins such as cingulin, vinculin, and integrins, among others. This figure is reprinted from a previous publication (Abdullahi et al., 2018), with permission from the previous publisher, the American Physiological Society.

Figure 3

Schematic of the affected areas of the brain after ischemic stroke. Closest to the location of the blood clot, and thus the loss of blood flow, is the infarct core, which contains irreversibly damaged tissue. Outside of the infarct core lies the penumbra, which also contains the benign oligemia, and defines the area of reversible tissue damage. While the benign oligemia specifies tissue that will recover function on its own, tissue within the penumbra but outside of the benign oligemia requires therapeutic intervention for full recovery.

Figure 4

The time course of BBB opening and associated expression of pro-inflammatory mediators of BBB damage. Initial opening of the BBB is likely caused, at least in part, by increases in MMPs, specifically MMP-2. This initial phase occurs over ~24 h and is referred to as “reversible.” Over time, continuous production of pro-inflammatory molecules, such as TNF-alpha, IL-1beta, and MMPs 3 and 9, can lead to prolonged opening (72+ h) of the BBB, potentially contributing to long-term tissue damage. This phase is thus referred to as “irreversible.” Reprinted from Yang and Rosenberg, “Matrix metalloproteinases as therapeutic targets for stroke,” Brain Research, 2015, 1,623:30–38, with permission from Elsevier.

Figure 5

Structure of the endothelial glycocalyx. The glycocalyx, a mechanotransducer implicated in BBB regulation, extends from the membrane of ECs into the vessel lumen and is largely composed of proteoglycans and glycoproteins. The proteoglycans consist of the core proteins, syndecans, and glypicans, along with their attached glycosaminoglycans: heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA). These chains are also modified by sialic acid (SA), which provides a net negative charge to the structure. Additionally, the glycocalyx contains glycoproteins, such as integrins and immunoglobulins, and soluble proteins, such as albumin. Reprinted from Harding et al., 2019 “Endothelial barrier reinforcement relies on flow-regulated glycocalyx, a potential therapeutic target,” Biorheology, 56 (2–3): 131–149, with permission from IOS Press. The publication is available at IOS Press through http://dx.doi.org/10.3233/BIR-180205.