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

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.

Bibliographic Details

Main Authors:	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
Format:	Artículo biblioteca
Language:	eng
Published:	Wiley 2022
Subjects:	TRPC6, ENFERMEDAD ATEROSCLEROTICA, RECEPTORES, CÉLULA MUSCULAR LISA VASCULAR, FOSFORILACIÓN,
Online Access:	https://repositorio.uca.edu.ar/handle/123456789/15358
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