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Purpose: Plaque stability is governed by it's collagen content and VSMC phenotype1. RGS5, a GPCR modulator, has been shown to be associated with plaque stability3. RGS5 may moderate VSMC/endothelial cell interactions4. We examined if RGS5 expression is associated with plaque stability and detailed its role in VSMC/HUVEC behavior in vitro. Methods: With IRB permission, samples from 91 patients undergoing carotid thrombendarterectomy were collected and RNA was extracted. Target-PCRs for RGS5 were normalized for PCR efficiency and 3 housekeeping genes (GAPDH, ATPsynthase, Tubulin) using qBase software. RGS5 was downregulated in human VSMC or HUVEC by siRNA. After 24h, cells were incubated with mytomicin-C for 1 hour, and the confluent monolayer was wounded. Wound closure percentage after 20h, of scrambled vs. RGS5 siRNA transfected VSMCs was measured (ImageJ). HUVECs conditioned medium was used to perform VSMC scratch assays. RGS5 expression in resident vs. migrated VSMCs was assessed by collecting the cells that had migrated off a confluent coverslip. RNA was extracted for qRT-PCR. RGS5 expression was normalized by HPRT using the Δ(ΔCT) method. Scrambeled and RGS5 siRNA transfected HUVECs were cocultured with VSMCs to produce spheroids in a 96 well plate (1:1 ratio, 3000 cell/well). Spheroids structure was scored 24 hours later for HUVEC coverage, spheroid shape and size. Results: RGS5-RNA was increased in stable compared to unstable plaques (3.1±0.5 vs 1.6±0.3 CNRQ, n=91, p