Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice

Takakuni Maki, Masafumi Ihara, Youshi Fujita, Takuo Nambu, Kazutoshi Miyashita, Mahito Yamada, Kazuo Washida, Keiko Nishio, Hidefumi Ito, Hiroshi Harada, Hideki Yokoi, Hiroshi Arai, Hiroshi Itoh, Kazuwa Nakao, Ryosuke Takahashi, Hidekazu Tomimoto

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background and Purpose- Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. Methods- A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. Results- After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. Conclusions- These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

Original languageEnglish
Pages (from-to)1122-1128
Number of pages7
JournalStroke
Volume42
Issue number4
DOIs
Publication statusPublished - 2011 Apr

Fingerprint

Adrenomedullin
Vascular Dementia
Perfusion
Carotid Stenosis
Fibroblast Growth Factor 2
Vascular Endothelial Growth Factor A
Oxidative Stress
Circle of Willis
Cerebrovascular Disorders
Cognitive Dysfunction
Common Carotid Artery
Memory Disorders
Short-Term Memory
Cognition
Blood Vessels
Up-Regulation
Endothelial Cells
White Matter
Brain

Keywords

  • adrenomedullin
  • angiogenesis
  • arteriogenesis
  • vascular dementia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice. / Maki, Takakuni; Ihara, Masafumi; Fujita, Youshi; Nambu, Takuo; Miyashita, Kazutoshi; Yamada, Mahito; Washida, Kazuo; Nishio, Keiko; Ito, Hidefumi; Harada, Hiroshi; Yokoi, Hideki; Arai, Hiroshi; Itoh, Hiroshi; Nakao, Kazuwa; Takahashi, Ryosuke; Tomimoto, Hidekazu.

In: Stroke, Vol. 42, No. 4, 04.2011, p. 1122-1128.

Research output: Contribution to journalArticle

Maki, T, Ihara, M, Fujita, Y, Nambu, T, Miyashita, K, Yamada, M, Washida, K, Nishio, K, Ito, H, Harada, H, Yokoi, H, Arai, H, Itoh, H, Nakao, K, Takahashi, R & Tomimoto, H 2011, 'Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice', Stroke, vol. 42, no. 4, pp. 1122-1128. https://doi.org/10.1161/STROKEAHA.110.603399
Maki, Takakuni ; Ihara, Masafumi ; Fujita, Youshi ; Nambu, Takuo ; Miyashita, Kazutoshi ; Yamada, Mahito ; Washida, Kazuo ; Nishio, Keiko ; Ito, Hidefumi ; Harada, Hiroshi ; Yokoi, Hideki ; Arai, Hiroshi ; Itoh, Hiroshi ; Nakao, Kazuwa ; Takahashi, Ryosuke ; Tomimoto, Hidekazu. / Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice. In: Stroke. 2011 ; Vol. 42, No. 4. pp. 1122-1128.
@article{24bae25efae6457eaa7151204065453f,
title = "Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice",
abstract = "Background and Purpose- Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. Methods- A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. Results- After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. Conclusions- These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.",
keywords = "adrenomedullin, angiogenesis, arteriogenesis, vascular dementia",
author = "Takakuni Maki and Masafumi Ihara and Youshi Fujita and Takuo Nambu and Kazutoshi Miyashita and Mahito Yamada and Kazuo Washida and Keiko Nishio and Hidefumi Ito and Hiroshi Harada and Hideki Yokoi and Hiroshi Arai and Hiroshi Itoh and Kazuwa Nakao and Ryosuke Takahashi and Hidekazu Tomimoto",
year = "2011",
month = "4",
doi = "10.1161/STROKEAHA.110.603399",
language = "English",
volume = "42",
pages = "1122--1128",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice

AU - Maki, Takakuni

AU - Ihara, Masafumi

AU - Fujita, Youshi

AU - Nambu, Takuo

AU - Miyashita, Kazutoshi

AU - Yamada, Mahito

AU - Washida, Kazuo

AU - Nishio, Keiko

AU - Ito, Hidefumi

AU - Harada, Hiroshi

AU - Yokoi, Hideki

AU - Arai, Hiroshi

AU - Itoh, Hiroshi

AU - Nakao, Kazuwa

AU - Takahashi, Ryosuke

AU - Tomimoto, Hidekazu

PY - 2011/4

Y1 - 2011/4

N2 - Background and Purpose- Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. Methods- A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. Results- After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. Conclusions- These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

AB - Background and Purpose- Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. Methods- A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. Results- After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. Conclusions- These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

KW - adrenomedullin

KW - angiogenesis

KW - arteriogenesis

KW - vascular dementia

UR - http://www.scopus.com/inward/record.url?scp=79954922055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79954922055&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.110.603399

DO - 10.1161/STROKEAHA.110.603399

M3 - Article

VL - 42

SP - 1122

EP - 1128

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 4

ER -