Differential expression of regulator of G-protein signaling 5 (RGS5) between arteries and veins as well as hypetension in RGS2 knockout mice suggests that RGS proteins may determine differential arterial responses to vasoactive GPCR agonists. To determine possible segmental specific GPCR regulation, expression of RGS R4 subfamily mRNAs was analyzed using real-time quantitative reverse transcription polymerase chain reaction (QRT-PCR) in different segments of the arterial tree in rats. RGS5 was both the most abundant RNA in this family and the most differentially expressed between segments. Among the R4s, expression of RGS5 mRNA was greatest in the common iliac artery, abdominal aorta (AA), pulmonary artery, and inferior vena cava.Compared with thoracic aorta (TA), AA had significantly greater mRNA expressions of RGS5 (10-fold), RGS3 (2.2-fold), RGS16 (1.8-fold), and. RGS4 (1.4-fold). Since the marked difference in expression of RGS 5 suggested a major difference in phenotype between the two segments of the aorta, we performed transcript profiling of these vessels, and identified 161 genes differentially expressed between these segments of aorta. The segments were also compared functionally. Consistent with the hypothesis that RGS5 blocks angiotensin receptor signaling via increased GTPase activity of G慣, force generation by aortic rings in response to angiotensin II, but not phenylephrine, was significantly less in AA than TA. Whole-cell voltage-gated K+ current (IKv) analysis, measured by patch clamp in freshly isolated smooth muscle cells (SMCs), revealed that IKv was significantly greater in AA SMCs compared with TA SMCs. Kv 1.5 mRNA was also more highly expressed in AA relative to TA. In vitro cultured rat arterial SMCs, transfected RGS5 demonstrated increases in Kv 1.2, Kv 1.5, and Kv 2.1 channel subunits mRNA in response to angiotensin II compared with negative control, suggesting that RGS 5 could be part of the differential control of expression of these potassium channels. This study reveals that arteries have distinct molecular signatures that likely give rise to unique physiological properties.