title: Deferoxamine, Cerebrovascular Hemodynamics, and Vascular Aging: Potential Role for Hypoxia-Inducible Transcription Factor-1-Regulated Pathways.
abstract: OBJECTIVE
  Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes.
  
  
  METHODS
  We assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform.
  
  
  RESULTS
  Deferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04).
  
  
  CONCLUSIONS
  Deferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.). fsorond@partners.org.
authors: Farzaneh A
authors: FA
authors: Sorond
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
authors: Can Ozan
authors: CO
authors: Tan
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
authors: Sarah
authors: S
authors: LaRose
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
authors: Andrew D
authors: AD
authors: Monk
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
authors: Raina
authors: R
authors: Fichorova
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
authors: Stanthia
authors: S
authors: Ryan
authors: From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
authors: Lewis A
authors: LA
authors: Lipsitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015913:Chelation Therapy / Q000379:methods*; D018592:Cross-Over Studies; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D004921:Erythropoietin / Q000097:blood*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D017262:Siderophores / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D016896:Treatment Outcome; D017585:Ultrasonography, Doppler, Transcranial; D042442:Vascular Endothelial Growth Factors / Q000097:blood / Q000187:drug effects*; D055815:Young Adult
chemical_list: D051793:Hypoxia-Inducible Factor 1; D017262:Siderophores; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D003676:Deferoxamine
keywords: aging; deferoxamine; hypoxia-inducible transcription factor-1; transcranial Doppler sonography