Dual role of PKA in phenotypic modulation of vascular smooth muscle cells by extracellular ATP

American Journal of Physiology. Cell Physiology
D Kyle HogarthNickolai O Dulin

Abstract

Extracellular ATP is released from activated platelets and endothelial cells and stimulates proliferation of vascular smooth muscle cells (VSMC). We found that ATP stimulates a profound but transient activation of protein kinase A (PKA) via purinergic P2Y receptors. The specific inhibition of PKA by adenovirus-mediated transduction of the PKA inhibitor (PKI) attenuates VSMC proliferation in response to ATP, suggesting a positive role for transient PKA activation in VSMC proliferation. By contrast, isoproterenol and forskolin, which stimulate a more sustained PKA activation, inhibit VSMC growth as expected. On the other hand, the activity of serum response factor (SRF) and the SRF-dependent expression of smooth muscle (SM) genes, such as SM-alpha-actin and SM22, are extremely sensitive to regulation by PKA, and even transient PKA activation by ATP is sufficient for their downregulation. Analysis of the dose responses of PKA activation, VSMC proliferation, SRF activity, and SM gene expression to ATP, with or without PKI overexpression, suggests the following model for the phenotypic modulation of VSMC by ATP, in which the transient PKA activation plays a critical role. At low micromolar doses, ATP elicits a negligible effect on D...Continue Reading

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Citations

Mar 28, 2008·Purinergic Signalling·David Erlinge, Geoffrey Burnstock
Sep 25, 2009·The Journal of Biological Chemistry·Sebastien TaurinNickolai O Dulin
Feb 2, 2006·Molecular and Cellular Biology·Jiyan ZhangAnning Lin
Mar 21, 2008·American Journal of Physiology. Cell Physiology·Sebastien TaurinNickolai O Dulin
Sep 26, 2009·Arteriosclerosis, Thrombosis, and Vascular Biology·Alicia L BlakerChristopher P Mack
Jan 20, 2009·American Journal of Respiratory Cell and Molecular Biology·Nathan SandboNickolai O Dulin
Dec 29, 2015·Histochemistry and Cell Biology·Ming-Jie ZhangLi-Li Zhang
Jun 17, 2011·Journal of Cellular Physiology·Chih-Chung LinChuen-Mao Yang
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Jan 7, 2017·Circulation Research·Geoffrey Burnstock
Feb 16, 2006·The Journal of Biological Chemistry·Sebastien TaurinNickolai O Dulin
Apr 13, 2013·The Journal of Biological Chemistry·Nathan SandboNickolai Dulin
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Nov 20, 2004·Molecular Pharmacology·Nathan SandboNickolai O Dulin
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Feb 5, 2014·The Journal of Biological Chemistry·Jacob KachNickolai O Dulin
Aug 23, 2011·American Journal of Physiology. Lung Cellular and Molecular Physiology·Nathan SandboNickolai O Dulin
Sep 27, 2021·Pflügers Archiv : European journal of physiology·Barbara MoserJakob Voelkl

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