PIP2 Upregulation Improves Capillary Blood Flow in the Brain
Reduced cerebral blood flow is an important component of loss of function in the aging brain. A number of different mechanisms contribute to this issue, including heart failure and thus a reduced ability to pump blood uphill to the brain, loss of capillary density with age, and various impairments in the small-scale regulation of blood flow via contraction and dilation of vessels. The research here focuses on mechanisms relevant to this latter vessel based control over blood flow, demonstrating a way in which these mechanisms can be manipulated to improve the flow of blood into the brain.
Brain capillaries are sensors of neural activity. When a brain region is active, capillary endothelial cells (ECs) sense neuron-derived mediators and elicit a local increase in blood flow (functional hyperemia) to support the rise in metabolic needs. This hyperemic response involves a rapid electrical component and a slower chemical component that involves Gαq PCR (GqPCR) activation by agonists released from neurons. The intravascular forces associated with hyperemia engage mechanosensitive Piezo1-mediated signaling that serves a mechano-feedback control function to facilitate the return of elevated blood flow to basal levels.
Whether GqPCR activity influences Piezo1 mechanosensitive signaling has not been explored, despite the potential significant implications of such crosstalk. Using patch-clamp electrophysiology and freshly isolated brain capillary ECs, we demonstrate that prostanoid or muscarinic GqPCR activation facilitates Piezo1 activity. Pharmacological studies revealed the involvement of Gαq and phospholipase C stimulation, as well as downstream phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis in Piezo1 activation.
Exogenous application of nanomolar-to-micromolar PIP2 suppressed Piezo1 open probability. Brain capillary ECs from mouse models of Alzheimer's disease, cerebral small vessel disease, or Piezo1 gain-of-function mutation exhibited higher Piezo1 activity, that was corrected by exogenous ex vivo PIP2 application. We finally tested in vivo the hypothesis that systemic PIP2 administration restores functional hyperemia in EC-specific Piezo1 gain-of-function mutant mice suffering impaired blood flow. Our findings provide insights into Piezo1 channel regulation and how it affects neurovascular coupling and cerebral blood flow.