Neuronal and vascular deficits following chronic adaptation to high altitude

Cramer, Nathan; Korotcov, Alexandru; Bosomtwi, Asamoah; Xu, Xiufen; Holman, Derek; Whiting, Kathleen; Jones, Scott C.; Hoy, Andrew R.; Dardzinski, Bernard J.; Galdzicki, Zygmunt

doi:10.1016/j.expneurol.2018.10.007

Cited by 26 publications

(33 citation statements)

References 94 publications

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“…Previous studies found that collaterogenesis in the embryo and collateral remodeling in the adult following arterial occlusion are reduced in mice deficient in either VEGF-A or Flk1. 12 As well, hypoxia increased Cxcr 4 expression ( Figure 4 ) and induced SDF1 expression, 32 , 33 and MCAO stimulated SDF1 release from a number of cell types that recruit immune and endothelial progenitor cells to regions undergoing neovascularization. 34 – 38 Furthermore, SDF1 and CXCR4 are required for collateral formation after occlusion of the dorsal aorta in zebrafish embryos.…”

Section: Resultsmentioning

confidence: 85%

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

Zhang

Rzechorzek

Aghajanian

et al. 2020

J Cereb Blood Flow Metab

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Pial collaterals provide protection in stroke. Evidence suggests their formation late during gestation (collaterogenesis) is driven by reduced oxygen levels in the cerebral watersheds. The purpose of this study was to determine if collaterogenesis can be re-activated in the adult to induce formation of additional collaterals (“neo-collateral formation”, NCF). Mice were gradually acclimated to reduced inspired oxygen (FIO2) and maintained at 12, 10, 8.5 or 7% for two-to-eight weeks. Hypoxemia induced “dose”-dependent NCF and remodeling of native collaterals, and decreased infarct volume after permanent MCA occlusion. In contrast, no formation occurred of addition collateral-like intra-tree anastomoses, PComs, or branches within the MCA tree. Hypoxic NCF, remodeling and infarct protection were durable, i.e. retained for at least six weeks after return to normoxia. Hypoxia increased expression of Hif2α, Vegfa, Rabep2, Angpt2, Tie2 and Cxcr4. Neo-collateral formation was abolished in mice lacking Rabep2, a novel gene involved in VEGFA→Flk1 signaling and required for formation of collaterals during development, and inhibited by knockdown of Vegfa, Flk1 and Cxcr4. Rabep2-dependent NCF was also induced by permanent MCA occlusion. This is the first report that hypoxia induces new pial collaterals to form. Hypoxia- and occlusion-induced neo-collateral formation provide models to study collaterogenesis in the adult.

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Section: Resultsmentioning

confidence: 85%

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

Zhang

Rzechorzek

Aghajanian

et al. 2020

J Cereb Blood Flow Metab

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“…There is also evidence that high and turbulent shear-stress, which may occur secondary to hyper-perfusion and reduced CaO 2 , can induce angiogenesis and vascular remodeling (241, 246, 247). Hypoxic exposure may additionally promote angiogenesis through several non-mechanic endothelial pathways (248), although these may be perturbed in SCD.…”

Section: Hemodynamic Compromisementioning

confidence: 99%

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

et al. 2019

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It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt and silent stroke, microstructural injury, and cognitive difficulties. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. Here, we review mechanistic pathways for which there is accumulating evidence and propose an integrative systems-biology framework for understanding neurological risk. Drawing upon work from other vascular beds in SCD, as well as the wider stroke literature, we propose that macro-circulatory hyper-perfusion, regions of relative micro-circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. We suggest that in this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke and/or microstructural injury if metabolic demand exceeds tissue oxygenation. This framework brings together recent developments in the field, highlights outstanding questions, and offers a first step toward a linking pathophysiological explanation of neurological risk that may help inform future screening and treatment strategies.

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“…Although neuroimaging studies suggest that multiple brain regions are impacted by HH exposure, the hippocampal formation is frequently identi ed as a site of injury during HH [43,44]. In rats, some early cytotoxic lesion and studies concluded that the hippocampus is dispensable for recognizing a familiar conspeci c [45,46]. HH induced alteration in hippocampus might be the reason behind alteration in social interaction behavior in rats.…”

Section: Discussionmentioning

confidence: 99%

COX-1/EP1R Inhibition Ameliorate Deficits in Adult Neurogenesis and Social Interaction via Alleviating NLRP3/ IL-1β Activation During Hypobaric Hypoxia

Chauhan¹,

Kumar²,

Roy³

et al. 2020

Preprint

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BackgroundLow oxygen environments like hypobaric hypoxia (HH) are common nodes to various diseases: characterized by neuroinflammation, which is detrimental to the structural and functional aspects of hippocampal circuitry. Various hypoxic conditions also lead to elevation of NLRP3 mediated neuroinflammation that may contribute to cognitive deficits. Components of neurogenic niches like microglia and astrocyte are largely affected by neuroinflammation; however, a systematic investigation of the impact of NLRP3 mediated neuroinflammation on components of neurogenic niche during hypoxia (HH) remains elusive. MethodsIn this study, we simulated cerebral hypoxia via decreasing partial pressure of oxygen(HH). The effect of hypobaric hypoxic (1, 3 and 7 day at 25000 ft) on social memory, anxiety, adult neurogenesis change in the inflammatory milieu in DG was explored in detail. We explored the efficacy of COX-1 inhibitor (Valery salicylate, 5mg/kg/day,i.p), and EP1R antagonist (SC19220, 1mg/kg/day,i.p) on NLRP3 mediated neuroinflammation and associated maladies during HH. ResultsWe observed that HH exposure induced alteration in social and anxiety-like behavior post 7 day exposure along with perturbation in levels of BDNF, Serotonin and adult neurogenesis in the DG right from day 1. Moreover, significant elevated NLRP3, caspase-1, and IL-1β levels are observed during HH from day 1. Concomitantly, a notable increase in the COX-1/EP1 pathway in both activated microglia and astrocyte in DG was evident after 3HH exposure. Pharmacological COX-1 inhibitor and EP1 antagonist counteract the detrimental effects of HH exposure on social memory, adult neurogenesis, and NLRP3 inflammasome induction. ConclusionsThus, our data showed induction of the COX-1/EP1 pathway in glial cells is detrimental to adult neurogenesis and social memory, raising possibility that the COX-1/EP1 pathway as a plausible target for inflammasome related neurogenesis impairment.

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Neuronal and vascular deficits following chronic adaptation to high altitude

Cited by 26 publications

References 94 publications

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

COX-1/EP1R Inhibition Ameliorate Deficits in Adult Neurogenesis and Social Interaction via Alleviating NLRP3/ IL-1β Activation During Hypobaric Hypoxia

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Neuronal and vascular deficits following chronic adaptation to high altitude

Cited by 26 publications

References 94 publications

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

COX-1/EP1R&nbsp;Inhibition Ameliorate Deficits in Adult Neurogenesis and Social Interaction via Alleviating NLRP3/ IL-1β Activation During Hypobaric Hypoxia

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COX-1/EP1R Inhibition Ameliorate Deficits in Adult Neurogenesis and Social Interaction via Alleviating NLRP3/ IL-1β Activation During Hypobaric Hypoxia