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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:2048.)
© 2003 American Heart Association, Inc.

Vascular Biology

Trans-Cellular Proliferating Cell Nuclear Antigen Gene Activation in Cerebral Vascular Smooth Muscle by Endothelial Oxidative Injury In Vivo

Volodymyr Gerzanich; Svetlana Ivanova; Michiel S. van der Heijden; Hui Zhou; J. Marc Simard

From the Departments of Neurosurgery (V.G., S.I., M.v.d.H., H.Z., J.M.S.), Physiology (J.M.S.), and Pathology (J.M.S.), University of Maryland School of Medicine, Baltimore, Md.

Correspondence to Dr J. Marc Simard, Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene St, Baltimore, MD 21201-1595. E-mail msimard{at}surgery1.umaryland.edu

Objective— This study was undertaken to assess the role of vascular smooth muscle cell (VSMC) Ca²⁺ channels and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in gene regulation after oxidative endothelial injury (OEI).

Methods and Results— OEI was produced by infusion of Na fluorescein (NaFluo) photoactivated by UV light immediately before intravenous injection. Posterior cerebral arteries were studied using immunofluorescence imaging, Western blotting, or patch clamping of isolated cells. After infusion of photoactivated NaFluo, but not NaFluo, (1) superoxide dismutase-1 (SOD-1) was upregulated in endothelium, consistent with oxidant stress; (2) the fraction of VSMC nuclei labeled for proliferating cell nuclear antigen (PCNA) increased 7-fold at 6 hours, preceded by a several-fold increase in nuclear phospho-cAMP-response element binding protein, with PCNA upregulation prevented by pretreatment with polyethylene glycol (PEG)-SOD; (3) in VSMCs, phospho-CaMKII increased 20-fold 5 minutes after OEI, with a 2-fold increase in peak Ca²⁺ channel currents; and (4) changes in cAMP-response element binding protein and PCNA were blocked by systemic administration of lipophilic (nifedipine) or hydrophilic (amlodipine) 1,4-dihydropyridine Ca²⁺ channel blockers, the calmodulin inhibitor trifluoperazine, or the CaMKII inhibitor KN-93, with none of these agents preventing SOD-1 upregulation in endothelium.

Conclusions— Activation of VSMC Ca²⁺ channels and CaMKII is a key early signaling event required for upregulation of PCNA gene expression in VSMCs after oxidative injury to endothelium.

Key Words: endothelium • vascular smooth muscle • oxidant stress • calcium channel • Ca²⁺/calmodulin-dependent protein kinase II

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