Yet, it was recently demonstrated that the blood-flow- associated forces, predominantly the level of shear stress, can profoundly affect the expression of tight junction proteins, thus regulating the strength of the endothelial barrier. It has been shown that increased shear stress, especially with pulsatile flow characteristics, upregulated pivotal tight junction proteins, such as occludin and ZO-1 in the cerebrovascular endothelium. Consequently, increased expression of these proteins was associated with reduced transendothelial permeability (Colgan et al., 2007). In parallel, loss of shear stress after flow cessation enhanced the blood-brain barrier permeability. (Krizanac-Bengez et al., 2006a; Krizanac-Bengez et al., 2006b)
Therefore, a reduced shear, for example due to the refluxing venous blood flow, could potentially result in the weakening of the blood-brain barrier. In addition, it has been found that steady shear stress upregulated the activity of the Na-K-Cl cotransporter in cerebral microvascular endothelium. Although it remains unclear whether this protein could control the integrity of the blood-brain barrier, it is suspected that it plays a role in the regulation of endothelial cell volume (Chang et al., 2008; Suvatne et al., 2001).
Basic Science Advances for Clinicians
Blood–Brain Barrier Breakdown in Acute and Chronic Cerebrovascular Disease
Yi Yang, MD, PhD;
Gary A. Rosenberg, MD
+ Author Affiliations
From the Departments of Neurology (Y.Y., G.A.R.), Neurosciences (G.A.R.), and Cell Biology and Physiology (G.A.R.), University of New Mexico Health Sciences Center, Albuquerque, NM.
Disruptions of the blood–brain barrier (BBB) and edema formation both play key roles in the development of neurological dysfunction in acute and chronic cerebral ischemia. Animal studies have revealed the molecular cascades that are initiated with hypoxia/ischemia in the cells forming the neurovascular unit and that contribute to cell death. Matrix metalloproteinases cause reversible degradation of tight junction proteins early after the onset of ischemia, and a delayed secondary opening during a neuroinflammatory response occurring from 24 to 72 hours after. Cyclooxygenases are important in the delayed opening as the neuroinflammatory response progresses. An early opening of the BBB within the 3-hour therapeutic window for tissue-type plasminogen activator can allow it to enter the brain and increase the risk of hemorrhage. Chronic hypoxic hypoperfusion opens the BBB, which contributes to the cognitive changes seen with lacunar strokes and white matter injury in subcortical ischemic vascular disease. This review will describe the molecular and cellular events associated with BBB disruption and potential therapies directed toward restoring the integrity of the neurovascular unit.
The resulting endothelial cells have many BBB attributes, including well-organized tight junctions, appropriate expression of nutrient transporters and polarized efflux transporter activity. Notably, they respond to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance (1,450 ± 140 Ω cm2), and they possess molecular permeability that correlates well with in vivo rodent blood-brain transfer coefficients.
"We now know that the blood-brain barrier also plays a vital role in the process by 'vacuuming' -- so to speak -- the brain fluid for extraneous glutamate, which is then pumped into the blood where it does not have a damaging effect. This is new knowledge that can have enormous impact on future drug development. We have charted a biological mechanism that other scientists eventually can try to influence chemically, for example, in the form of medicine to limit cell death after a stroke. When the brain lacks oxygen, the glutamate level in the brain fluid increases dramatically, which kick starts a toxic chain reaction that kills cells," explains Associate Professor Birger Brodin.
The research results have just been published in the scientific journal GLIA.
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