Pericyte K_ATP channel hyperactivity redistributes cortical blood flow in a CADASIL mouse model

Area of Science:

• Neuroscience
• Vascular Biology
• Aging Research

Background:

• Cerebral hemodynamic dysfunction drives unhealthy brain aging.
• Impaired microcirculatory reactivity causes uneven brain perfusion, increasing vulnerability in deeper regions and contributing to cognitive decline.
• The specific role of capillaries in these deficits is poorly understood.

Purpose of the Study:

• To investigate the role of capillaries in cerebral hemodynamic dysfunction during brain aging.
• To elucidate the mechanisms underlying impaired microcirculatory reactivity and deep-layer hypoperfusion.
• To identify potential therapeutic targets for age-related cognitive decline.

Main Methods:

• Spatial transcriptomics to analyze gene expression in specific brain layers.
• In vivo two-photon and three-photon imaging to measure layer-specific cerebral blood flow.
• Electrophysiology, ex vivo, and in silico approaches to study pericyte function and KATP channel activity.

Main Results:

• Downregulation of ATP-synthesizing genes indicates microvascular metabolic impairment and paralleled impaired pericyte bioenergetics.
• Reduced arteriolar-capillary tone and diminished deep-layer perfusion were observed.
• Hyperactive KATP channels in pericytes redistribute blood flow to superficial layers, causing deep-layer hypoperfusion.

Conclusions:

• Microvascular metabolic impairment and pericyte energy deficits disrupt spatial perfusion equalization.
• This loss of perfusion equalization contributes to deep-layer hypoperfusion and cognitive decline in aging.
• Targeting pericyte bioenergetics and KATP channel activity may represent a tractable approach to address age-related brain dysfunction.