Inhibition of transient receptor potential cation channel 6 promotes capillary arterialization during post-ischaemic blood flow recovery

• Autores: Numaga-Tomita, Takuro; Shimauchi, Tsukasa; Kato, Yuri; Nishiyama, Kazuhiro; Nishimura, Akiyuki; Sakata, Kosuke; Inada, Hiroyuki; Kita, Satomi; Iwamoto, Takahiro; Nabekura, Junichi; Birnbaumer, Lutz; Mori, Yasuo; Nishida, Motohiro
• Año de publicación: 2022
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: British Journal of Pharmacology, 2022
• Materia: TRPC6; ENFERMEDAD ATEROSCLEROTICA; RECEPTORES; CÉLULA MUSCULAR LISA VASCULAR; FOSFORILACIÓN
• Institución: Pontificia Universidad Católica Argentina

Fil: Numaga-Tomita, Takuro. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón
Fil: Numaga-Tomita, Takuro. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón
Fil: Numaga-Tomita, Takuro. The Graduate University for Advanced Studies. School of Life Science. SOKENDAI; Japón
Fil: Numaga-Tomita, Takuro. Shinshu University School of Medicine; Japón
Fil: Shimauchi, Tsukasa. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón
Fil: Shimauchi, Tsukasa. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón
Fil: Shimauchi, Tsukasa. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón
Fil: Shimauchi, Tsukasa. Kyushu University. Graduate School of Medical Sciences; Japón
Fil: Kato, Yuri. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón
Fil: Nishiyama, Kazuhiro. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón
Fil: Nishimura, Akiyuki. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón
Fil: Nishimura, Akiyuki. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón
Fil: Nishimura, Akiyuki. The Graduate University for Advanced Studies. School of Life Science. SOKENDAI; Japón
Fil: Sakata, Kosuke. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón
Fil: Inada, Hiroyuki. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón
Fil: Kita, Satomi. Fukuoka University. Faculty of Medicine; Japón
Fil: Kita, Satomi. Tokushima Bunri University. Faculty of Pharmaceutical Sciences; Japón
Fil: Iwamoto, Takahiro. Fukuoka University. Faculty of Medicine; Japón
Fil: Nabekura, Junichi. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón
Fil: Birnbaumer, Lutz. Research Triangle Park. National Institutes of Health. National Institute of Environmental Health Sciences; Estados Unidos
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Mori, Yasuo. Kyoto University. Graduate School of Engineering; Japón
Fil: Nishida, Motohiro. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón
Fil: Nishida, Motohiro. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón
Fil: Nishida, Motohiro. The Graduate University for Advanced Studies. School of Life Science. SOKENDAI; Japón
Fil: Nishida, Motohiro. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón
Abstract: Background and Purpose: Capillary arterialization, characterized by the coverage of pre-existing or nascent capillary vessels with vascular smooth muscle cells (VSMCs), is critical for the development of collateral arterioles to improve post-ischaemic blood flow. We previously demonstrated that the inhibition of transient receptor potential 6 subfamily C, member 6 (TRPC6) channels facilitate contractile differentiation of VSMCs under ischaemic stress. We here investigated whether TRPC6 inhibition promotes post-ischaemic blood flow recovery through capillary arterialization in vivo. Experimental Approach: Mice were subjected to hindlimb ischaemia by ligating left femoral artery. The recovery rate of peripheral blood flow was calculated by the ratio of ischaemic left leg to non-ischaemic right one. The number and diameter of blood vessels were analysed by immunohistochemistry. Expression and phosphorylation levels of TRPC6 proteins were determined by western blotting and immunohistochemistry. Key Results: Although the post-ischaemic blood flow recovery is reportedly dependent on endothelium-dependent relaxing factors, systemic TRPC6 deletion significantly promoted blood flow recovery under the condition that nitric oxide or prostacyclin production were inhibited, accompanying capillary arterialization. Cilostazol, a clinically approved drug for peripheral arterial disease, facilitates blood flow recovery by inactivating TRPC6 via phosphorylation at Thr69 in VSMCs. Furthermore, inhibition of TRPC6 channel activity by pyrazole-2 (Pyr2; BTP2; YM-58483) promoted post-ischaemic blood flow recovery in Apolipoprotein E-knockout mice. Conclusion and Implications: Suppression of TRPC6 channel activity in VSMCs could be a new strategy for the improvement of post-ischaemic peripheral blood circulation.