PIP₂ corrects an endothelial Piezo1 channelopathy.

Area of Science:

• Neuroscience
• Vascular Biology
• Cell Physiology

Background:

• Brain capillaries, specifically endothelial cells (ECs), act as sensors of neural activity, regulating cerebral blood flow through functional hyperemia.
• Functional hyperemia involves Gαq protein-coupled receptor (GqPCR) activation and mechanosensitive Piezo1 signaling, but the interplay between them is unknown.

Purpose of the Study:

• To investigate the influence of GqPCR activation on Piezo1 mechanosensitive signaling in brain capillary ECs.
• To elucidate the molecular mechanisms underlying this crosstalk and its implications for neurovascular coupling.

Main Methods:

• Patch-clamp electrophysiology on freshly isolated brain capillary ECs.
• Pharmacological manipulation of GqPCR and downstream signaling pathways.
• Assessment of Piezo1 activity in ECs from disease models and in vivo functional hyperemia studies.

Main Results:

• GqPCR activation by prostanoids or muscarinic agonists potentiates Piezo1 channel activity.
• This potentiation involves Gαq, phospholipase C, and phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis; exogenous PIP2 suppresses Piezo1 activity.
• ECs from Alzheimer's disease and cerebral small vessel disease models show elevated Piezo1 activity, correctable by PIP2.

Conclusions:

• GqPCR signaling crosstalks with and enhances Piezo1 activity in brain capillary ECs, mediated by PIP2 levels.
• Dysregulated Piezo1 activity in disease states can be modulated by PIP2.
• Findings offer insights into Piezo1 regulation, neurovascular coupling, and potential therapeutic strategies for cerebral blood flow disorders.