Journal
CELLS
Volume 11, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/cells11132041
Keywords
canonical transient receptor potential 6; peripheral arterial disease; vessel maturation; 1-benzilpiperadine
Categories
Funding
- JST CREST [JPMJCR2024 (20348438)]
- JSPS KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology [21H05269, 22H02772, 19K07116, 22K06842]
- Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED [JP 22ama121031]
- National Research Foundation of Korea (NRF) - Korean government (MSIP) [2017K1A1A2004511]
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Inhibition of TRPC6 channel activity in vascular smooth muscle cells promotes blood flow recovery in peripheral artery disease. The drug 1-BP can inhibit this channel activity, leading to improved peripheral circulation and skeletal muscle mass. Additionally, 1-BP can increase vascular nitric oxide bioavailability and enhance blood flow recovery in patients with endothelial dysfunction.
Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1-benzilpiperadine derivative (1-BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1-BP-treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind-limb ischemia (HLI) in mice. 1-BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6-deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1-BP. 1-BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1-BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.
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