One area of BBB maintenance that has received limited attention is its regulation via endothelial mechanotransduction, the conversion of mechanical forces into endothelial cell (EC) biochemical signals ( Lam et al., 2012).

Therefore, it is necessary to develop therapeutic strategies protecting against BBB dysfunction. Structural injury of TJs combined with BBB transporter dysfunction can collectively lead to increased paracellular solute permeability, ultimately resulting in tissue edema and exacerbating brain injury associated with cognitive impairment ( Abdullahi et al., 2018). The mechanisms of BBB damage in the setting of stroke include modification of tight junction (TJ) proteins, modulation of transporters expression, and inflammatory damage ( Abdullahi et al., 2018). It is well established that one of the hallmarks of acute ischemic stroke is the disruption of the blood-brain barrier (BBB Sifat et al., 2017), which leads to the subsequent disruption of ion homeostasis and transporter functions in the brain. The majority of observed strokes are classified as ischemic strokes, which occur when a clot within a blood vessel interrupts the cerebral blood flow that supplies vital ions, oxygen, and nutrients to the brain ( Obermeier et al., 2013). In the United States alone, approximately 800,000 people suffer from stroke yearly, accounting for $34 billion in medical expenses and lost productivity ( Kassner and Merali, 2015 Shi et al., 2016). Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.Дespite significant progression in treatment strategies, stroke remains one of the most common causes of death worldwide and accounts for 55% of all neurological disabilities ( Posada-Duque et al., 2014). 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. 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. 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. 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. It is thus vital for the maintenance of central nervous system homeostasis. The BBB along with its supportive cells, collectively referred to as the вЂњneurovascular unit,вЂќ is the brainвЂ™s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB).

5Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, United States.

4Department of Chemical Engineering, Northeastern University, Boston, MA, United States.

3Center for Innovations in Wound Healing Research, Tufts University School of Medicine, Boston, MA, United States.

2Department of Development, Molecular, and Chemical Biology, Tufts Sackler School of Graduate Biomedical Sciences, Boston, MA, United States.

1Department of Bioengineering, Northeastern University, Boston, MA, United States.

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