期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2025998118
关键词
functional hyperemia; cerebral small vessel diseases; CADASIL; potassium channel; PIP2
资金
- American Heart Association [17POST33650030, 20CDA35310097, 14SDG20150027, 17SDG33670237]
- Cardiovascular Research Institute at the University of Vermont
- CADASIL Together We Have Hope nonprofit organization
- Totman Medical Research Trust
- Center forWomen's Health Research located at the University of Colorado Anschutz Medical Campus
- University of Pennsylvania Orphan Disease Center in partnership with the cureCADASIL
- Fondation Leducq Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain
- European Union [666881]
- French National Agency of Research [ANR-16-RHUS-0004]
- National Institute of Neurological Disorders and Stroke
- National Institute of Aging [R01-NS-110656]
- National Institute of Diabetes and Digestive and Kidney Diseases [R37-DK-053832]
- National Institute of General Medical Sciences [P20-GM-135007]
- Principle Investigators Mary Cushman and Mark Nelson, Vermont Center for Cardiovascular and Brain Health
- National Heart, Lung, and Blood Institute [R01-HL136636, P01-HL-095488, R01-HL-121706, 7UM-HL-1207704, R01HL-131181, R35-HL-140027]
- Agence Nationale de la Recherche (ANR) [ANR-16-RHUS-0004] Funding Source: Agence Nationale de la Recherche (ANR)
Research suggests that impaired functional hyperemia in cerebral small vessel diseases is caused by decreased activity of Kir2.1 channels, which is linked to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2). Systemic injection of soluble PIP2 has shown promising results in restoring functional hyperemia in SVD mice, providing a potential strategy for treating brain disorders with disrupted blood flow.
Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K+ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.
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