Loss of myeloid Bmal1 exacerbates hypertensive vascular remodelling through interaction with STAT6 in mice . Issue 13 (2nd November 2021)

• Record Type: Journal Article
• Authors: Huo, Mingyu; Cao, Xiaoyun; Zhang, Hongsong; Lau, Chi Wai; Hong, Huiling; Chen, Francis M; Huang, Yu; Chawla, Ajay; Tian, Xiao Yu
• Is Part Of: Cardiovascular research. Volume 118:Issue 13(2022)
• Page Start: 2859
• Page End: 2874
• Publication Date: 2021-11-02
• Subjects: Macrophage -- Vascular remodelling -- Hypertension -- BMAL1 -- STAT6; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvab336
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. Methods and results: Wild type Bmal1 f/f and myeloid cell selective Bmal1 knockout Bmal1 f/f ; LysM Cre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1 f/f ; LysM Cre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1 f/f ; LysM Cre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4ra f/f ; LysM Cre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. Conclusions: Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling. Graphical Abstract: