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(Circulation Research. 2005;96:873.)
© 2005 American Heart Association, Inc.

Cellular Biology

[Ca²⁺]_i Reduction Increases Cellular Proliferation and Apoptosis in Vascular Smooth Muscle Cells

Relevance to the ADPKD Phenotype

Sertac N. Kip, Larry W. Hunter, Qun Ren, Peter C. Harris, Stefan Somlo, Vicente E. Torres, Gary C. Sieck, Qi Qian

From the Division of Nephrology and Hypertension (S.N.K., Q.R., P.C.H., V.E.T., Q.Q.), Department of Physiology and Biomedical Engineering (L.W.H., G.C.S.), Mayo Clinic College of Medicine, Rochester, Minn; and Section of Nephrology (S.S.), Department of Medicine, Yale University School of Medicine, New Haven, Conn.

Correspondence to Qi Qian, MD, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail qian.qi{at}mayo.edu

Cardiovascular complications are the leading cause of morbidity and mortality in autosomal dominant polycystic kidney disease. Pkd2^+/– vascular smooth muscle cells (VSMCs) have an abnormal phenotype and defective intracellular Ca²⁺ ([Ca²⁺]_i) regulation. We examined cAMP content in vascular smooth muscles from Pkd2^+/– mice because cAMP is elevated in cystic renal epithelial cells. We found cAMP concentration was significantly increased in Pkd2^+/– vessels compared with wild-type vessels. Furthermore, reducing the wild-type VSMC [Ca²⁺]_i by Verapamil or BAPTA-AM significantly increased cellular cAMP concentration (mainly by phosphodiesterase [PDE] inhibition), the rate of VSMC proliferation (determined by direct cell counting, ³H-incorporation, FACS analysis of cells entering S phase, and quantitative Western PCNA and ERK1/2 analyses), and the rate of apoptosis (by Hoechst staining, FACS analysis of the Annexin-V positive cells, and quantitative Western Bax, cytochrome c, and activated caspase 9 and 3 analyses). The low [Ca²⁺]_i induced VSMC proliferation was independent of cAMP/B-Raf signaling, while that of apoptosis was promoted by cAMP. In summary, Pkd2^+/– VSMCs have elevated cAMP levels. This elevation can also be induced by reducing [Ca²⁺]_i in wild-type VSMCs. The [Ca²⁺]_i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype.

Key Words: cAMP • phosphodiesterase • proliferation • ERK • apoptosis

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