Defining the critical hypoxic threshold that promotes vascular remodeling in the brain

Abstract

In animal models, hypoxic pre-conditioning confers protection against subsequent neurological insults, mediated in part through an extensive vascular remodeling response. In light of the therapeutic potential of this effect, the goal of this study was to establish the dose-response relationship between level of hypoxia and the extent of cerebrovascular modeling, and to define the mildest level of hypoxia that promotes remodeling. Mice were exposed to different levels of continuous hypoxia (8-21% O2) for seven days before several aspects of vascular remodeling were evaluated, including endothelial proliferation, total vascular area, arteriogenesis, and fibronectin/α5β1 integrin expression. For most events, the threshold level of hypoxia that stimulated remodeling was 12-13% O2. Interestingly, many parameters displayed a biphasic dose-response curve, with peak levels attained at 10% O2, but declined thereafter. Further analysis in the 12-13% O2 range revealed that vascular remodeling occurs by two separate mechanisms: (i) endothelial hyperplasia, triggered by a hypoxic threshold of 13% O2, which leads to increased capillary growth, and (ii) endothelial hypertrophy, triggered by a more severe hypoxic threshold of 12% O2, which leads to expansion of large vessels and arteriogenesis. Taken together, these results define the hypoxic thresholds for vascular remodeling in the brain, and point to two separate mechanisms mediating this process.

Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection

“…There is a temporal component of the hormetic response, as effects of a highly stressful exposure are typically seen 24 to 72 hours later, and usually present as a modest overcompensation response in which the net result is about 30% to 60% greater than the original starting point or control group value. Such hormetic responses, which are sometimes referred to as a “ceiling response,” may also describe the modest degree of stimulation in the low dose zone (Calabrese et al, ; Calabrese ; Abete et al, ; Boroujerdi and Milner, ).…”

“…For example, following injury, chemical signaling to induce cellular repair processes has been shown to be dependent upon endogenous mechanisms that display concentration gradients that act in a biphasic hormetic pattern (Calabrese, ; Abete et al, ). Similarly, hormetic dose–concentration responses are seen in endothelial cells that interact with the vascular capillary system to optimize biological activities (Boroujerdi and Milner, ).…”

“…Considerable evidence now exists to demonstrate that several agents that have been successfully tested in preclinical trials to prevent damage from stroke, traumatic brain injury, and acute or chronic memory loss (e.g., in AD and other dementing disorders) act via hormetic dose–response mechanisms to elicit diverse but interacting cellular processes that evoke cellular, and broader, system‐wide processes of repair and recovery (Calabrese, ). As matter of fact, all of the drugs currently approved by the US Food and Drug Administration to reduce signs and symptoms of AD have been shown to display hormetic dose–response patterns of effect (Boroujerdi and Milner, ).…”

Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia

“…It is possible that individuals repeatedly exposed to subacute hypoxia/ischemia 399 may respond differently to nitrate supplementation due to hypoxic preconditioning. Studies suggest that 400 repeated subacute hypoxic exposure may offer neurovascular protection(Poinsatte et al 2015), 401 cerebrovascular remodeling(Boroujerdi and Milner 2015), and may improve oxygen 402 saturation(Foster et al 2014) and abrogate oxidative stress(Berger et al 2015) during additional 403 ischemic events. Whether hypoxic preconditioning alters the effect of nitrate on NVC and cognitive 404 function in hypoxia was beyond the scope of the current study and requires future research.…”

Obstructive Sleep Apnea in Neurodegenerative Disorders: Current Evidence in Support of Benefit from Sleep Apnea Treatment

“…On the other hand, one study conducted on elderly women with OSA found that risk of mild cognitive impairment and cognitive decline was associated with a higher oxygen desaturation index [23], although another study did not reach the same conclusion, possibly because it included mostly mild to moderate OSA [25]. One possible explanation for the discrepant findings concerning the impact of hypoxemia on brain function could relate to different patterns of chronic intermittent versus more sustained hypoxemia, as well as the severity of hypoxemia [104,118,119].…”