PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity

Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2025998118. doi: 10.1073/pnas.2025998118.


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.

Keywords: CADASIL; PIP2; cerebral small vessel diseases; functional hyperemia; potassium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Cerebral Small Vessel Diseases / etiology*
  • Cerebral Small Vessel Diseases / metabolism
  • Cerebrovascular Circulation*
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Hyperemia / etiology*
  • Hyperemia / metabolism
  • Male
  • Mice, Transgenic
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Potassium Channels, Inwardly Rectifying / metabolism*


  • Kir2.1 channel
  • Phosphatidylinositol 4,5-Diphosphate
  • Potassium Channels, Inwardly Rectifying