Elsevier

Journal of Vascular Surgery

Volume 40, Issue 3, September 2004, Pages 519-528
Journal of Vascular Surgery

Regulator of G protein signaling 5 marks peripheral arterial smooth muscle cells and is downregulated in atherosclerotic plaque

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Objective

Regulator of G protein signaling 5 (RGS5), an inhibitor of Gα(q) and Gα(i) activation, was recently identified among genes highly expressed in smooth muscle cells (SMCs) of aorta but not vena cava. This finding prompted the hypothesis that RGS5 provides long-term G protein inhibition specific to normal arterial SMC populations and that loss of expression may in turn contribute to arterial disease.

Methods

To test this hypothesis we characterized RGS5 gene expression throughout the vasculature of nonhuman primates to determine whether RGS5 was restricted to arteries in other vascular beds and whether expression was altered in arterial disease.

Results

In situ hybridization localized RGS5 message to medial SMCs of peripheral arteries, including carotid, iliac, mammary, and renal arteries, but not accompanying veins. SMCs of many small arteries and arterioles also expressed RGS5, including glomerular afferent arterioles critical to blood pressure regulation. Differential expression persisted in culture, inasmuch as RGS5 message was significantly higher in SMCs derived from arteries than from veins at real-time polymerase chain reaction. It was remarkable that the only major arterial bed lacking RGS5 was the coronary circulation. In atherosclerotic peripheral arteries RGS5 was expressed in medial SMCs, but was sharply downregulated in plaque SMCs.

Conclusion

These data identify RGS5 as a new member of a short list of genes uniquely expressed in peripheral arteries but not coronary arteries. Persistence of an arterial pattern of RGS5 expression in culture and lack of expression in coronary arteries support a unique SMC phenotype fixed by distinct lineage or differentiation pathways. The association between loss of expression and arterial wall disease has prompted the new hypothesis that prolonged inhibition by RGS5 of vasoactive or trophic G protein signaling is critical to normal peripheral artery function.

Clinical relevance

Peripheral arterial disease and its treatment largely parallel that of the coronary bed, despite varying results of specific interventions. Differences in disease patterns and responses to treatment may vary as a result of fundamental differences in cell behavior at specific sites within the arterial tree related to developmental phenotypes and varied progenitor populations. Exploring diversity among smooth muscle cell (SMC) populations at the level of gene expression, we identified regulator of G protein signaling 5 (RGS5), an inhibitor of G protein signaling, as a gene expressed in SMCs of arteries but not veins. Our present data further restrict its importance to peripheral artery SMCs in contrast to a lack of expression in the coronary bed. In addition, RGS5 was downregulated in atherosclerotic plaque SMCs. These data, along with our previous observation that RGS5 is downregulated in graft neointimal SMCs, suggest a role for RGS5 in regulating SMC growth in peripheral arteries, a new hypothesis to be tested in future studies.

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Supported by grants RO1HL57557 (R.L.G.) and PO1HL003174 (S.M.S.) from the National Institutes of Health. Dr Geary is a Brooks Scholar of Wake Forest University.

Competition of interest: none.