Aims: Arterial diseases are freqeuntly specific to different segments and smooth muscle cells (SMCs) of different branches have distinct embryological origin. we undertook a systematic effort to determine the extent of differences in gene expression between the thoracic aorta (TA) and the abdominal aorta (AA). We also correlated these expression differences with physiologic function. Methods and Results: We utilized whole genome gene expression microarrays to compare expression patterns in the rat TA and AA. We identified 161 differentially expressed genes between these two segments. Functional analysis of differences in expression by Gene Set Enrichment Analysis identified different categories of genes enriched in each section of the aorta. For example, GPCR-related genes are overrepresented in the AA, while the TA showed dramatic enrichment of gene categories linked to mitochondria and energy generation. Because GPCR functions are implicated in many vascular diseases, we confirmed the differential expression of the arterial specific Regulator of G-protein signaling – 5 (RGS5), and extended the analysis to additional members of the RGS-R4 subfamily. RGS5 was the most abundant RGS-R4 mRNA in the AA, and it was the most differentially expressed family member across all vascular beds. To analyze functional correlates to the differential expression of RGS5, we performed aortic ring contraction assays from the TA and AA. Consistent with the hypothesis that RGS5 blocks angiotensin II (Ang II) type 1 receptor signaling via increased G-mediated GTPase activity, Ang II-induced force generation was significantly lower in AA relative to TA. Furthermore, whole-cell voltage-gated K+ current (IKv) analysis revealed that IKv was significantly greater in SMCs from the AA compared to cells from TA. Kv1.5 mRNA was more highly expressed in the AA relative to the TA. Conclusions: The differential gene expression pattern between TA and AA suggests distinct differentiation pathways may explain regional specificity of arterial diseases. Specifically, the enrichment of GPCR-related genes in the AA and mitochondrial genes in the TA may account for the diverse physiological function of these two distinct vascular segments