Abstract
We recently demonstrated that when mice are exposed to chronic mild hypoxia (CMH, 8% O2), blood vessels in the spinal cord show transient vascular leak that is associated with clustering and activation of microglia around disrupted vessels. Importantly, microglial depletion profoundly increased hypoxia-induced vascular leak, implying that microglia play a critical role maintaining vascular integrity in the hypoxic spinal cord. The goal of the current study was to examine if microglia play a similar vasculo-protective function in the brain. Employing extravascular fibrinogen leak as an index of blood–brain barrier (BBB) disruption, we found that CMH provoked transient vascular leak in cerebral blood vessels that was associated with activation and aggregation of Mac-1-positive microglia around leaky vessels. Interestingly, CMH-induced vascular leak showed regional selectivity, being much more prevalent in the brainstem and olfactory bulb than the cerebral cortex and cerebellum. Pharmacological depletion of microglia with the colony stimulating factor-1 receptor inhibitor PLX5622, had no effect under normoxic conditions, but markedly increased hypoxia-induced cerebrovascular leak in all regions examined. As in the spinal cord, this was associated with endothelial induction of MECA-32, a marker of leaky CNS endothelium, and greater loss of endothelial tight junction proteins. Brain regions displaying the highest levels of hypoxic-induced vascular leak also showed the greatest levels of angiogenic remodeling, suggesting that transient BBB disruption may be an unwanted side-effect of hypoxic-induced angiogenic remodeling. As hypoxia is common to a multitude of human diseases including obstructive sleep apnea, lung disease, and age-related pulmonary, cardiac and cerebrovascular dysfunction, our findings have important translational implications. First, they point to a potential pathogenic role of chronic hypoxia in triggering BBB disruption and subsequent neurological dysfunction, and second, they demonstrate an important protective role for microglia in maintaining vascular integrity in the hypoxic brain.
Highlights
Compared to other organs, blood vessels in the central nervous system (CNS) have uniquely high electrical resistance and low permeability, which is thought to protect sensitive neural cells from potentially harmful components in the blood [1, 18, 33]
In mice exposed to Chronic mild hypoxia (CMH), microglial depletion results in cerebrovascular loss of endothelial tight junction proteins Endothelial tight junction proteins are a critical part of the molecular machinery responsible for the high vascular integrity observed in the CNS [1, 18, 33]; we investigated if microglial absence influences cerebrovascular expression of two important tight junction proteins: zonula occludens-1 (ZO-1) and occludin in the brainstem region
Our findings confirm that CMH triggers transient vascular leak in the brain just as it does in the spinal cord, which provokes a microglial vasculo-protective response
Summary
Blood vessels in the central nervous system (CNS) have uniquely high electrical resistance and low permeability, which is thought to protect sensitive neural cells from potentially harmful components in the blood [1, 18, 33]. In the brain, this is referred to as the blood–brain barrier (BBB), and loss of BBB integrity is a common feature of a broad spectrum of neurological conditions, including meningitis, ischemic stroke, multiple sclerosis (MS), and CNS tumours [2, 10, 15, 22, 34]. Is BBB integrity compromised during exposure to mild hypoxia; second, if vascular integrity is disrupted, does this phenomenon display regional vulnerability; and third, do microglia play a vasculoprotective function in the brain?
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