Inhibition of transient receptor potential cation channel 6 promotes capillary arterialization during post‐ischaemic blood flow recovery. (3rd October 2022)

• Record Type: Journal Article
• 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
• Is Part Of: British journal of pharmacology. Volume 180:Number 1(2023)
• Page Start: 94
• Page End: 110
• Publication Date: 2022-10-03
• Subjects: channel -- peripheral arterial disease -- phosphorylation -- transient receptor potential -- vascular smooth muscle cell; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15942
• Languages: English
• ISSNs: 0007-1188

Abstract

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 A polipoprotein 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. Abstract : Transient receptor potential canonical 6 ( T rpc 6 )‐knockout (KO) (C6(−/−)) mice has better blood flow recovery after hindlimb ischaemia than wild type (C6(+/+)) mice. Vascular smooth muscle‐specific rescue of TRPC6 expression reverses that. * P < 0.05. TRPC6 inhibition by Pyr2 facilitates blood flow recovery after hindlimb ischaemia in hypercholesterolemic Apo E‐KO mice. * P < 0.05.