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Updated: May 30, 2025
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
Endothelial TRIM35-Regulated MMP10 Release Exacerbates Calcification of Vascular Grafts
Yiming Leng1, Wei Wang1, Jun Lu2
1Clinical Research Center, Postdoctoral Station of Clinical Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, P. R. China.
Insights
Vascular calcification after surgery is linked to endothelial TRIM35, which normally prevents it. Loss of TRIM35 increases MMP10, causing severe calcification in grafts, suggesting MMP10 as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Vascular Remodeling
- Cellular Signaling
Background:
- Vascular calcification significantly increases morbidity and mortality in cardiovascular disease (CVD).
- The mechanisms driving vascular graft calcification, especially endothelial-smooth muscle cell (SMC) interactions, remain poorly understood.
- Endothelial tripartite motif 35 (TRIM35) expression is upregulated during arterial isograft remodeling.
Purpose of the Study:
- To investigate the role of endothelial TRIM35 in vascular calcification following arterial isograft surgery.
- To elucidate the interaction between endothelial cells (ECs) and SMCs in the context of vascular graft remodeling.
- To identify potential therapeutic targets for preventing vascular calcification in grafts.
Main Methods:
- Single-cell analysis of wild-type mice using an arterial isograft model.
- Generation and analysis of TRIM35 conditional endothelial knockout (cKO) mice.
- In vitro co-culture assays with SMCs and TRIM35 knockout endothelium in calcified medium.
- Investigation of the noncanonical NF-κB signaling pathway and Matrix Metalloproteinase 10 (MMP10) secretion.
Main Results:
- TRIM35 deficiency in endothelial cells led to severe vascular calcification in artery grafts.
- TRIM35 knockout endothelium induced calcium deposition in co-cultured SMCs.
- This calcification was mediated by increased secretion of MMP10.
- Endothelial TRIM35 inhibits MMP10 via K63-linked ubiquitination of RelB, affecting noncanonical NF-κB signaling.
Conclusions:
- Endothelial TRIM35 plays a crucial inhibitory role in vascular calcification during arterial isograft remodeling.
- Aberrant endothelial MMP10 secretion is a key driver of vascular calcification in TRIM35-deficient grafts.
- Targeting the MMP10 pathway presents a potential therapeutic strategy for vascular calcification in vessel grafts.
Abstract:
Vascular calcification is a highly regulated process in cardiovascular disease (CVD) and is strongly correlated with morbidity and mortality, especially in the adverse stage of vascular remodeling after coronary artery bypass graft surgery (CABG). However, the pathogenesis of vascular graft calcification, particularly the role of endothelial-smooth muscle cell interaction, is still unclear. To test how ECs interact with SMCs in artery grafts, single-cell analysis of wild-type mice is first performed using an arterial isograft mouse model and found robust cytokine-mediated signaling pathway activation and SMC proliferation, together with upregulated endothelial tripartite motif 35 (TRIM35) expression. Unexpectedly, severe SMC calcification in artery grafts is found in TRIM35 conditional endothelial knockout (cKO) mice. Calcified medium (comprising calcium chloride and beta-glycerophosphate)-induced calcium deposition in vitro is also found in SMCs cocultured with TRIM35 knockout endothelium. This extraordinary phenomenon is further confirmed to be induced by increased MMP10 secretion. Mechanistically, endothelial TRIM35 inhibits MMP10 expression and secretion by promoting K63-linked ubiquitination of RelB and maintaining its nuclear localization, consequently inhibiting nuclear transcription of MMP10 through the noncanonical NF-κB signaling pathway. Targeting MMP10 in situ in arterial isografts can effectively alleviate vascular calcification caused by conditional endothelial TRIM35 knockout. These findings demonstrated that TRIM35 inhibited vascular calcification during arterial isograft remodeling, a process that is driven by the aberrant secretion of endothelial MMP10. Targeting MMP10 pathway may be a potential therapeutic strategy for vascular calcification in vessel grafts.
