A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia.

Area of Science:

• Cardiovascular Biology
• Pharmacology
• Vascular Biology

Background:

• Peripheral artery disease (PAD) is characterized by impaired blood flow due to arterial occlusion.
• Limited pharmacological treatments exist for PAD, necessitating novel therapeutic strategies.
• Transient Receptor Potential Canonical (TRPC) 6 channels in vascular smooth muscle cells (VSMCs) are implicated in vascular function.

Purpose of the Study:

• To investigate the therapeutic potential of 1-benzilpiperadine derivative (1-BP), a TRPC3 and TRPC6 inhibitor, for PAD.
• To elucidate the role of TRPC6 channel inhibition in promoting vascular repair and blood flow recovery.

Main Methods:

• Administration of 1-BP to mice subjected to hind-limb ischemia (HLI) model.
• Assessment of capillary arterialization, peripheral circulation, and skeletal muscle mass.
• Evaluation of 1-BP effects in TRPC6-deficient mice and hypercholesterolemic mice with endothelial dysfunction.

Main Results:

• 1-BP treatment induced VSMC differentiation and improved blood flow recovery after HLI.
• 1-BP facilitated capillary arterialization and enhanced skeletal muscle regeneration.
• The beneficial effects of 1-BP were dependent on TRPC6, and it improved vascular nitric oxide bioavailability.

Conclusions:

• Selective inhibition of TRPC6 channels by 1-BP promotes vascular repair and blood flow recovery in PAD models.
• 1-BP demonstrates potential as a therapeutic agent for PAD by targeting vascular TRPC6 channels.
• The findings suggest a retrograde interaction from VSMCs to endothelium, contributing to improved vascular function.