CHRONIC INTERMITTENT HYPOXIA, NEUROVASCULAR DYSFUNCTION AND STROKE

Summary

Principal Investigator: Costantino Iadecola
Abstract: DESCRIPTION (provided by applicant): Sleep-disordered breathing, including sleep apnea (SA), is characterized by cyclical interruption of breathing during sleep, often caused by intermittent airway obstruction. SA is emerging as a highly prevalent cause of death and disability. In addition to hypertension and cardiac diseases, SA is an independent risk factor for stroke, and increases its incidence by 2-4 folds. The development of mechanism-based therapies has been hampered by the lack of insight into how SA increases the risk of cerebrovascular insufficiency and stroke. Although the pathophysiology of SA is likely to be multifactorial, chronic intermittent hypoxia (CIH) caused by the apneic episodes is considered a critical factor in the cardiovascular complications. In the systemic circulation, CIH, like SA, alters vascular function, but little is known about the impact of these alterations on the regulation of organ blood flow and on end-organ damage, particularly in brain. Considering the brain's unique susceptibility to vascular insufficiency, disruption of the regulation of the cerebral blood supply by CIH could compromise the delivery of adequate blood flow to the tissue and promote ischemic injury. The present proposal will test the central hypothesis that CIH exerts its deleterious effect on the brain by altering key cerebrovascular homeostatic mechanisms, reducing vascular reserves and increasing the vulnerability of the brain to ischemia. In particular, we will test the following specific hypotheses in four aims: (1) CIH disrupts the delivery of blood to the brain by altering vital regulatory mechanisms that assure adequate cerebral perfusion, such as functional hyperemia and cerebrovascular autoregulation;(2) CIH exerts its deleterious cerebrovascular effects by inducing vascular oxidative stress through the superoxide producing enzyme NADPH oxidase;(3) Upregulation of endothelin-1 in cerebral blood vessels, via ETA receptors, plays a major role in the neurovascular dysfunction;(4) The detrimental cerebrovascular effects of CIH deplete cerebrovascular reserves, aggravate the brain ischemia induced by middle cerebral artery occlusion, and increase the resulting tissue damage. These hypotheses will be tested using a mouse model of CIH and well-established approaches to examine cerebrovascular regulation and ischemic brain injury. The results of the proposed studies will provide new insights that may advance our understanding of the cerebrovascular complications of SA. PUBLIC HEALTH RELEVANCE: Disorders of breathing during sleep, including sleep apnea, have emerged as independent risk factors for stroke, especially silent strokes. The proposed studies will advance our understanding of the pathophysiological substrates underlying the increased susceptibility to ischemic injury in sleep apnea. Ultimately, the results of the proposed studies may suggest novel mechanism-based approaches to prevent or treat the deleterious effects of this highly prevalent condition.
Funding Period: 2011-04-01 - 2016-02-29
more information: NIH RePORT

Top Publications

  1. pmc Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia
    Carmen Capone
    Division of Neurobiology, Department of Neurology and Neuroscience, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
    Hypertension 60:106-13. 2012
  2. pmc Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury
    Krithi Irmady
    Department of Medicine and Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065, and Interdisciplinary Center for Neurosciences, Department of Neuroanatomy, University of Heidelberg, INF 307, D69120 Heidelberg, Germany
    J Neurosci 34:3419-28. 2014
  3. pmc Predicting future brain tissue loss from white matter connectivity disruption in ischemic stroke
    Amy Kuceyeski
    From the Department of Radiology A K, A R, Brain and Mind Research Institute A K, H K, B B N, A R, C I, and Department of Neurology H K, B B N, C I, Weill Cornell Medical College, New York, NY
    Stroke 45:717-22. 2014
  4. pmc Water deprivation induces neurovascular and cognitive dysfunction through vasopressin-induced oxidative stress
    Giuseppe Faraco
    Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA
    J Cereb Blood Flow Metab 34:852-60. 2014
  5. pmc Progranulin deficiency promotes post-ischemic blood-brain barrier disruption
    Katherine Jackman
    Brain and Mind Research Institute, Departments of Radiology and Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10021
    J Neurosci 33:19579-89. 2013
  6. pmc The pathobiology of vascular dementia
    Costantino Iadecola
    Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA Electronic address
    Neuron 80:844-66. 2013
  7. pmc Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation
    Giuseppe Faraco
    Brain and Mind Research Institute, 407 E 61st St, Room 303, New York, NY 10065
    Hypertension 62:759-66. 2013
  8. pmc Lipoprotein receptor-related protein-6 protects the brain from ischemic injury
    Takato Abe
    Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA
    Stroke 44:2284-91. 2013
  9. pmc Genetic deletion of CD36 enhances injury after acute neonatal stroke
    Moon Sook Woo
    Department of Neurology, University of California at San Francisco, San Francisco, CA 94158, USA
    Ann Neurol 72:961-70. 2012
  10. pmc Brain-immune interactions and ischemic stroke: clinical implications
    Hooman Kamel
    Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
    Arch Neurol 69:576-81. 2012

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  2. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
  3. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
  4. Cell Free O2 Carriers: Cerebrovascular Control and Stroke
    RAYMOND CHARLES KOEHLER; Fiscal Year: 2013

Detail Information

Publications13

  1. pmc Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia
    Carmen Capone
    Division of Neurobiology, Department of Neurology and Neuroscience, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
    Hypertension 60:106-13. 2012
    ..The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain's susceptibility to cerebral ischemia...
  2. pmc Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury
    Krithi Irmady
    Department of Medicine and Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065, and Interdisciplinary Center for Neurosciences, Department of Neuroanatomy, University of Heidelberg, INF 307, D69120 Heidelberg, Germany
    J Neurosci 34:3419-28. 2014
    ..These results identify miR-592 as a key regulator of p75(NTR) expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury. ..
  3. pmc Predicting future brain tissue loss from white matter connectivity disruption in ischemic stroke
    Amy Kuceyeski
    From the Department of Radiology A K, A R, Brain and Mind Research Institute A K, H K, B B N, A R, C I, and Department of Neurology H K, B B N, C I, Weill Cornell Medical College, New York, NY
    Stroke 45:717-22. 2014
    ..We hypothesized that the Network Modification Tool could predict remote brain tissue loss caused by poststroke loss of connectivity...
  4. pmc Water deprivation induces neurovascular and cognitive dysfunction through vasopressin-induced oxidative stress
    Giuseppe Faraco
    Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA
    J Cereb Blood Flow Metab 34:852-60. 2014
    ..The ensuing cerebrovascular dysregulation may alter cognitive function and increase the brain's susceptibility to cerebral ischemia. ..
  5. pmc Progranulin deficiency promotes post-ischemic blood-brain barrier disruption
    Katherine Jackman
    Brain and Mind Research Institute, Departments of Radiology and Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10021
    J Neurosci 33:19579-89. 2013
    ..Such a novel vasoprotective role of PGRN may contribute to brain dysfunction and damage in conditions associated with reduced PGRN function...
  6. pmc The pathobiology of vascular dementia
    Costantino Iadecola
    Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA Electronic address
    Neuron 80:844-66. 2013
    ..Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia. ..
  7. pmc Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation
    Giuseppe Faraco
    Brain and Mind Research Institute, 407 E 61st St, Room 303, New York, NY 10065
    Hypertension 62:759-66. 2013
    ..The ET1-induced cerebrovascular dysfunction may increase cerebrovascular risk by lowering cerebrovascular reserves and increasing the vulnerability of the brain to cerebral ischemia...
  8. pmc Lipoprotein receptor-related protein-6 protects the brain from ischemic injury
    Takato Abe
    Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA
    Stroke 44:2284-91. 2013
    ..However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6+/- mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia...
  9. pmc Genetic deletion of CD36 enhances injury after acute neonatal stroke
    Moon Sook Woo
    Department of Neurology, University of California at San Francisco, San Francisco, CA 94158, USA
    Ann Neurol 72:961-70. 2012
    ..We investigated the effects of genetic deletion of CD36 (CD36ko) on acute injury, and oxidative and inflammatory signaling after neonatal stroke...
  10. pmc Brain-immune interactions and ischemic stroke: clinical implications
    Hooman Kamel
    Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
    Arch Neurol 69:576-81. 2012
    ....
  11. pmc Reperfusion rather than ischemia drives the formation of ubiquitin aggregates after middle cerebral artery occlusion
    Karin Hochrainer
    Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
    Stroke 43:2229-35. 2012
    ..Here we investigate the relationship between ubiquitin aggregation and duration of ischemia/reperfusion, infarct volume, and proteasomal activity in a mouse model of focal ischemia...
  12. pmc Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury
    Katherine A Jackman
    From the Feil Family Brain and Mind Research Institute K A J, P Z, G F, P M P, C C, V P, G M, C I and Department of Radiology H U V, Weill Cornell Medical College, New York and Department of Natural Sciences, Baruch College, City University of New York P M P
    Stroke 45:1460-7. 2014
    ..Here, we tested the hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury...

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  3. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  4. Cell Free O2 Carriers: Cerebrovascular Control and Stroke
    RAYMOND CHARLES KOEHLER; Fiscal Year: 2013
    ....