期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 34, 期 12, 页码 1887-1897出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2014.156
关键词
blood-brain barrier; cerebral blood flow; dementia; neuroinflammation; TRPC; VCI
资金
- American Heart Association
- Oklahoma Center for the Advancement of Science and Technology
- Hungarian National Science Research Fund (OTKA) [K 108444]
- grant: Developing Competitiveness of Universities in the South Transdanubian Region, 'Identification of new biomarkers..' [SROP-4.2.2.A-11/1/KONV-2012-0017]
- grant: Developing Competitiveness of Universities in the South Transdanubian Region 'Complex examination of neuropeptide..' [SROP-4.2.2.A-11/1/KONV-2012-0024]
- National Center for Complementary and Alternative Medicine [R01-AT006526]
- National Institute on Aging [R01-AG038747, R01-NS056218, 1RO1-AG047879-01]
- Ellison Medical Foundation
- NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE [R01AT006526] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS056218] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG038747, R01AG047879] Funding Source: NIH RePORTER
Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-Induced tone of middle cerebral arteries (MC-As) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs, and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of-the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially-exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.
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