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Brain and circulating levels of A?1-40 differentially contribute to vasomotor dysfunction in the mouse brain.

ABSTRACT: Amyloid-? (A?), a peptide that accumulates in the brain and circulates in the blood of patients with Alzheimer disease, alters the regulation of cerebral blood flow and may contribute to the brain dysfunction underlying the dementia. However, the contributions of brain and circulating A?1-40 to the vascular dysfunction have not been elucidated.We used transgenic mice overexpressing mutated forms of the amyloid precursor protein in which A?1-40 is elevated in blood and brain (Tg-2576) or only in brain (Tg-SwDI). Mice were equipped with a cranial window, and the increase in cerebral blood flow induced by neural activity (whisker stimulation), or by topical application of endothelium-dependent vasodilators, was assessed by laser-Doppler flowmetry.The cerebrovascular dysfunction was observed also in Tg-SwDI mice, but despite ?40% higher levels of brain A?1-40, the effect was less marked than in Tg-2576 mice. Intravascular administration of A?1-40 elevated plasma A?1-40 and enhanced the dysfunction in Tg-SwDI mice, but not in Tg-2576 mice.The results provide evidence that A?1-40 acts on distinct luminal and abluminal vascular targets, the deleterious cerebrovascular effects of which are additive. Furthermore, the findings highlight the importance of circulating A?1-40 in the cerebrovascular dysfunction and may provide insight into the cerebrovascular alterations in conditions in which elevations in plasma A?1-40 occur.

SUBMITTER: Park L

PROVIDER: S-EPMC3530010 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Brain and circulating levels of Aβ1-40 differentially contribute to vasomotor dysfunction in the mouse brain.

Park Laibaik L Zhou Ping P Koizumi Kenzo K El Jamal Sleiman S Previti Mary Lou ML Van Nostrand William E WE Carlson George G Iadecola Costantino C

Stroke 20121129 1

<h4>Background and purpose</h4>Amyloid-β (Aβ), a peptide that accumulates in the brain and circulates in the blood of patients with Alzheimer disease, alters the regulation of cerebral blood flow and may contribute to the brain dysfunction underlying the dementia. However, the contributions of brain and circulating Aβ1-40 to the vascular dysfunction have not been elucidated.<h4>Methods</h4>We used transgenic mice overexpressing mutated forms of the amyloid precursor protein in which Aβ1-40 is el ...[more]

PMID: 23204056

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Project description:ObjectivesCardiopulmonary bypass-induced endothelial dysfunction has been inferred by changes in pulmonary vascular resistance, alterations in circulating biomarkers, and postoperative capillary leak. Endothelial-dependent vasomotor dysfunction of the systemic vasculature has never been quantified in this setting. The objective of the present study was to quantify acute effects of cardiopulmonary bypass on endothelial vasomotor control and attempt to correlate these effects with postoperative cytokines, tissue edema, and clinical outcomes in infants.DesignSingle-center prospective observational cohort pilot study.SettingPediatric cardiac ICU at a tertiary children's hospital.PatientsChildren less than 1 year old requiring cardiopulmonary bypass for repair of a congenital heart lesion.InterventionNone.Measurements and main resultsLaser Doppler perfusion monitoring was coupled with local iontophoresis of acetylcholine (endothelium-dependent vasodilator) or sodium nitroprusside (endothelium-independent vasodilator) to quantify endothelial-dependent vasomotor function in the cutaneous microcirculation. Measurements were obtained preoperatively, 2-4 hours, and 24 hours after separation from cardiopulmonary bypass. Fifteen patients completed all laser Doppler perfusion monitor (Perimed, Järfälla, Sweden) measurements. Comparing prebypass with 2-4 hours postbypass responses, there was a decrease in both peak perfusion (p = 0.0006) and area under the dose-response curve (p = 0.005) following acetylcholine, but no change in responses to sodium nitroprusside. Twenty-four hours after bypass responsiveness to acetylcholine improved, but typically remained depressed from baseline. Conserved endothelial function was associated with higher urine output during the first 48 postoperative hours (R = 0.43; p = 0.008).ConclusionsCutaneous endothelial dysfunction is present in infants immediately following cardiopulmonary bypass and recovers significantly in some patients within 24 hours postoperatively. Confirmation of an association between persistent endothelial-dependent vasomotor dysfunction and decreased urine output could have important clinical implications. Ongoing research will explore the pattern of endothelial-dependent vasomotor dysfunction after cardiopulmonary bypass and its relationship with biochemical markers of inflammation and clinical outcomes.

Project description:BackgroundYKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers.AimTo determine the longitudinal relation of circulating YKL-40 to levels and decline of lung function in the general population.MethodsWe used longitudinal data from up to 13 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972 and 1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL-40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function.ResultsData on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p = 0.05) faster than subjects in the third quartile, 5 ml/yr (p = 0.02) faster than subjects in the second quartile, and 10 ml/yr (p < 0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined, the top YKL-40 quartile was associated with a 9 ml/yr (p = 0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p = 0.35).ConclusionsCirculating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking.

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Brain and circulating levels of A?1-40 differentially contribute to vasomotor dysfunction in the mouse brain.

Publications

Brain and circulating levels of Aβ1-40 differentially contribute to vasomotor dysfunction in the mouse brain.

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