Ca2+ signaling, TRP channels, and endothelial permeability

Area of Science:

• Vascular Biology
• Cell Signaling
• Ion Channels

Background:

• Endothelial permeability increases during inflammation, leading to edema.
• Inflammatory mediators elevate intracellular calcium ([Ca2+]i) by activating G protein-coupled receptors.
• This calcium increase triggers cytoskeletal reorganization and VE-cadherin disassembly, compromising endothelial barrier function.

Purpose of the Study:

• To investigate the role of Transient Receptor Potential (TRP) channels in agonist-induced endothelial permeability.
• To elucidate the specific TRP channel isoforms involved in calcium signaling pathways regulating endothelial barrier function.

Main Methods:

• Studied calcium signaling pathways in endothelial cells, including inositol 1,4,5-trisphosphate (IP3) generation and store-operated calcium channels (SOCs).
• Investigated the expression and function of TRPC1 and TRPC4 channels in human and mouse endothelial cells.
• Utilized TRPC4 knockout mouse models to assess the impact on vascular responses and endothelial permeability.

Main Results:

• TRPC1 is identified as a key component of SOCs in human vascular endothelial cells, potentiating thrombin-induced permeability.
• TRPC4 knockout mice exhibit impaired store-operated calcium influx and reduced endothelium-dependent vasodilation.
• TRPC4 deficiency prevents endothelial cell retraction and reduces lung microvascular permeability increases in response to protease-activated receptor-1 (PAR-1) activation.

Conclusions:

• Endothelial TRP channels, particularly TRPC1 and TRPC4, are critical regulators of agonist-induced increases in endothelial permeability.
• TRPC channels play a significant role in inflammatory responses affecting vascular integrity.