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This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 294/2/H839    most recent 00587.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ray, J. B. Articles by Ward, M. E. PubMed PubMed Citation Articles by Ray, J. B. Articles by Ward, M. E.

Oxygen regulation of arterial smooth muscle cell proliferation and survival

¹Institute of Medical Science, ²Toronto General Hospital Research Institute and The Heart and Stroke/Richard Lewar Centre of Excellence, ⁴Department of Medical Biophysics, University of Toronto; ⁵Division of Respirology, Department of Medicine, St. Micheal's Hospital and the University of Toronto; ³Terrence Donnelly Vascular Biology Laboratories, ⁶Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada

Submitted 18 May 2007 ; accepted in final form 28 November 2007

The purpose of this study was to determine if hypoxia elicits different proliferative and apoptotic responses in systemic arterial smooth muscle cells incubated under conditions that do or do not result in cellular ATP depletion and whether these effects are relevant to vascular remodeling in vivo. Gene expression profiling was used to identify potential regulatory pathways. In human aortic smooth muscle cells (HASMCs) incubated at 3% O₂, proliferation and progression through the G1/S interphase are enhanced. Incubation at 1% O₂ reduced proliferation, delayed G1/S transition, increased apoptotic cell death, and is associated with mitochondrial membrane depolarization and reduced cellular ATP levels. In aorta and mesenteric artery from rats exposed to hypoxia (10% O₂, 48 h), both proliferation and apoptosis are increased, as are medial nuclear density and smooth muscle cell content. Although nuclear levels of hypoxia-inducible factor 1- (HIF-1) are increased to a similar extent in HASMCs incubated at 1 and 3% O₂, expression of tumor protein p53, its transcriptional target p21, as well as their regulatory factors and downstream effectors, are differentially affected under these two conditions, suggesting that the bidirectional effects of hypoxia are mediated by this pathway. We conclude that hypoxia induces a state of enhanced cell turnover through increased rates of both smooth muscle cell proliferation and death. This confers the ability to remodel the vasculature in response to changing tissue metabolic needs while avoiding the accumulation of mutations that may lead to malignant transformation or the formation of abnormal vascular structures.

systemic circulation; cell cycle; apoptosis