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Updated: Oct 14, 2025
Assessing Murine Resistance Artery Function Using Pressure Myography
Published on: June 7, 2013
Loss of myeloid Bmal1 exacerbates hypertensive vascular remodelling through interaction with STAT6 in mice
Mingyu Huo1,2, Xiaoyun Cao1, Hongsong Zhang1,3
1School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China.
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 Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ 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 Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ 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 Il4raf/f; LysMCre/+ 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.
Insights
BMAL1 deletion in vascular macrophages worsens hypertension and vascular remodeling by promoting a pro-fibrotic M2 phenotype. This enhances IL4-STAT6 signaling, leading to increased MMP9/MMP13 expression and collagen deposition.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Vascular macrophages play a role in hypertension and vascular remodeling.
- The specific phenotype and behavior of vascular macrophages in hypertension are not fully understood.
- BMAL1's contribution to macrophage phenotype in hypertensive vascular remodeling requires investigation.
Purpose of the Study:
- To investigate the role of BMAL1 in the pro-fibrotic phenotype of vascular macrophages during hypertension.
- To determine how BMAL1 influences vascular remodeling and blood pressure increase in a hypertensive model.
- To elucidate the molecular mechanisms by which BMAL1 affects macrophage signaling in hypertension.
Main Methods:
- Utilized wild type and myeloid cell-specific Bmal1 knockout mice infused with AngII to induce hypertension.
- Assessed blood pressure, vascular media thickness, vascular dysfunction, and macrophage phenotype (M2).
- Analyzed expression of MMP9, MMP13, collagen deposition, and STAT6 activation in response to IL4 in macrophages.
Main Results:
- BMAL1 deficiency in myeloid cells exacerbated AngII-induced hypertension, vascular remodeling, and dysfunction.
- Loss of BMAL1 promoted a pro-fibrotic M2 macrophage phenotype, increasing MMP9/MMP13 expression and collagen deposition.
- BMAL1 deletion enhanced IL4-induced STAT6 activation in macrophages, suggesting an inhibitory role for BMAL1 in this pathway.
- Deletion of myeloid IL4Rα attenuated hypertension and vascular remodeling in AngII-infused mice.
Conclusions:
- BMAL1 deletion promotes hypertensive vascular remodeling.
- BMAL1 may inhibit IL4-STAT6 signaling in macrophages by interacting with STAT6, thereby reducing STAT6 activation and target gene transcription (MMP9, MMP13).
- This mechanism contributes to vascular remodeling in hypertension.
