– Document – differential responses of blood-brain barrier associated cells to hypoxia and ischemia a comparative study anoxic brain injury

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Authors: sabrina engelhardt [1]; sheng-fu huang [1]; shalmali patkar [1]; max gassmann [1]; omolara O ogunshola (corresponding author) [1] background brain neurons require a stable environment and high nutrient supply for proper functioning [1]. In this regard, the well-coordinated teamwork of the cells at the blood?Brain barrier (BBB) is indispensable. Endothelial cells that line barrier vessels have intimate contact with supporting pericytes and astrocytes, as well as microglia, neurons and a well-defined extracellular matrix to fulfill their gatekeeper function at the BBB, crucially controlling nutrient supply and homeostatic balance [2].

It has become very apparent that these endothelial cells depend on inductive signaling of the surrounding cell types to fully develop and maintain their unique barrier phenotype [3, 4].Anoxic brain injury recently the important contribution of perivascular astrocytes and pericytes to BBB induction and maintenance has received increasing attention (for review see [5]). Hypoxia (reduced tissue oxygenation) severely impairs BBB function in vivo and in vitro [6, 7, 8] causing pathophysiological changes including disturbed energy balance and water/ion homeostasis [5], inflammatory events and leakage of blood-proteins into the brain [5]. Similarly ischemia, being characterized by impaired nutrient and O 2 supply, also results in significant BBB breakdown [9, 10]. Clearly, during injury conditions specific responses of astrocytes and pericytes impact BBB maintenance and brain function. Both astrocytes and pericytes have been shown to support barrier function via tight junction retention and reduction of endothelial cell death under hypoxic conditions [6, 11, 12, 13, 14].Anoxic brain injury on the contrary, both cell types up-regulate barrier permeabilizing factors in response to hypoxia/ischemia such as vascular endothelial growth factor (VEGF), cytokines, and matrix metalloproteinases (mmps) [15]. Currently we do not understand well how, or from where, the differential signals that alter BBB characteristics originate, although some evidence suggests that injury severity and duration determines the functional outcome of hypoxic/ischemic insults on BBB tightness [5, 16, 17]. In this regard hypoxia-inducible factor 1 (HIF-1), a central regulator of hypoxic/ischemic responses, is of particular importance. HIF-1 constitutes a heterodimeric transcription factor composed of the hypoxia-inducible HIF-1?Anoxic brain injury subunit and the constitutively expressed HIF-1? Subunit [18]. HIF-1 mediates hypoxic adaptation through transcriptional control of more than 100 genes participating in angiogenesis, proliferation and cellular metabolism to reduce O 2 consumption and increase O 2 supply but can also trigger cell death [18, 19]. Notably, the ability of different cell types to adapt to hypoxic/ischemic stress varies considerably. Neurons for example are very sensitive to such insults, whereas other brain cells such as astrocytes are far more resistant [1]. Our previous study showed that astrocytes and pericytes differentially modulate BBB permeability at varying severities of hypoxic insults [6], implying that insult severity likely triggers individual cell-specific responses with subsequent consequences on barrier modulation.Anoxic brain injury to gain better knowledge of cell-specific behavior in terms of overall tolerance as well as potential signaling to surrounding cells, we directly compared basal responses of individual BBB associated cells (brain microvascular endothelial cell line and primary rat endothelial cells (ecs), pericytes (pcs) and astrocytes (acs) to hypoxic and…