Abstract 383: STIM1 Deficiency in Vascular Smooth Muscle Cells Promotes Vascular Calcification in Atherosclerosis
Vascular calcification is a characteristic feature of atherosclerosis. We and others have demonstrated that osteogenic differentiation of vascular smooth muscle cells (VSMC) contribute predominantly to the pathogenesis of vascular calcification in atherosclerosis. The key cellular event that leads to calcification is the secretion of matrix vesicles (MVs). However, the molecular regulation of MV release and the causal effect of MV release on VSMC calcification are poorly understood. The objective of this study is to investigate the function of a key calcium flux regulator, stromal interaction molecule 1 (STIM1), in regulating MV release and VSMC calcification; and to elucidate the underlying molecular mechanisms. SMC-specific STIM1-deficient mice (STIM1Δ/Δ SMC) were generated by breeding SM22α-Cre mice with STIM1 smooth muscle floxed mice (STIM1f/f). In vitro characterization using primary VSMC isolated from STIM1Δ/Δ SMC and the control STIM1f/f mice demonstrated that STIM1 deletion promoted VSMC calcification, although STIM1 deficiency has been linked to decreased calcium signals in smooth muscle cells. Increased release of MVs was demonstrated with the STIM1Δ/Δ SMC VSMC compared with the control STIM1f/f VSMC. Using the atherogenic ApoE-/- model, we demonstrated that SMC-specific STIM1 deficiency increased atherosclerotic vascular calcification in vivo. Consistently, increased MVs were determined in the serum of the STIM1Δ/Δ SMC mice. Mechanistically, we found that STIM1 deficiency did not affect VSMC proliferation and survival, but decreased the expression of SMC-specific α-actin. The size of MVs released from STIM1f/f and STIM1Δ/Δ SMC VSMC appeared similar. However, MVs from the STIM1Δ/Δ SMC VSMC contained a greater amount of calcium compared with those from the STIM1f/f VSMC. Furthermore, immunofluorescent staining identified a rearrangement of actin-filament structure in the STIM1Δ/Δ VSMC, a critical cellular event that controls the release of MVs. These studies have determined a new causative effect of VSMC-expressed STIM1 on atherosclerotic vascular calcification; and identified a novel link connecting STIM1 and actin-cytoskeleton rearrangement in regulating MV release and vascular calcification.
Author Disclosures: Y. Yang: None. Y. Sun: None. Y. Chen: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2016 by American Heart Association, Inc.