HB-EGF depolarizes hippocampal arterioles to restore myogenic tone in a genetic model of small vessel disease.
Mech Ageing Dev
; 192: 111389, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-33127441
ABSTRACT
Vascular cognitive impairment, the second most common cause of dementia, profoundly affects hippocampal-dependent functions. However, while the growing literature covers complex neuronal interactions, little is known about the sustaining hippocampal microcirculation. Here we examined vasoconstriction to physiological pressures of hippocampal arterioles, a fundamental feature of small arteries, in a genetic mouse model of CADASIL, an archetypal cerebral small vessel disease. Using diameter and membrane potential recordings on isolated arterioles, we observed both blunted pressure-induced vasoconstriction and smooth muscle cell depolarization in CADASIL. This impairment was abolished in the presence of voltage-gated potassium (KV1) channel blocker 4-aminopyridine, or by application of heparin-binding EGF-like growth factor (HB-EGF), which promotes KV1 channel down-regulations. Interestingly, we observed that HB-EGF induced a depolarization of the myocyte plasma membrane within the arteriolar wall in CADASIL, but not wild-type, arterioles. Collectively, our results indicate that hippocampal arterioles in CADASIL mice display a blunted contractile response to luminal pressure, similar to the defect we previously reported in cortical arterioles and pial arteries, that is rescued by HB-EGF. Hippocampal vascular dysfunction in CADASIL could then contribute to the decreased vascular reserve associated with decreased cognitive performance, and its correction may provide a therapeutic option for treating vascular cognitive impairment.
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Base de dados:
MEDLINE
Assunto principal:
Arteríolas
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Canais de Potássio de Abertura Dependente da Tensão da Membrana
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Fator de Crescimento Semelhante a EGF de Ligação à Heparina
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Hipocampo
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article