Danielle A Jeffrey, Eric Prince, Niloufar Khakpour, Hannah R Ferris, Colin H. Peters, Gregory Seedorf, Phinea Z. Romero, Mayra Guerrero, Abigail N. Russell, Katherine Glodoski, Gregory L. Futia, Stephanie Bonney, Michael A. Thornton, Gregory L. Futia, Catherine Proenza, Anastacia M. Garcia, Nikolaos M. Tsoukias, Fabrice Dabertrand
Abstract Cerebral hemodynamic dysfunction is a key driver of unhealthy brain aging. Impaired microcirculatory reactivity leads to uneven perfusion, rendering deeper brain regions more vulnerable and thereby contributing to cognitive decline. Yet how capillaries contribute to these deficits remains poorly defined. Here we combined spatial transcriptomics with in vivo two-photon and three-photon imaging to measure layer-specific cerebral blood flow in control and small vessel disease model mice (CADASIL TgNotch3R169C). We found downregulation of ATP-synthesizing genes, indicating microvascular metabolic impairment that paralleled impaired pericyte bioenergetics. This energy deficit coincided with diminished tone in the arteriole–capillary transitional zone and reduced deep-layer perfusion. Complementary electrophysiology, ex vivo and in silico approaches, revealed that hyperactive K ATP channels in pericytes drive a redistribution of cerebral blood flow toward superficial cortical layers. This loss of spatial perfusion equalization, despite preserved global flow, contributed to deep-layer hypoperfusion, establishing a previously underrecognized but tractable vascular function disrupted in aging pathology.