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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1754.)
© 2003 American Heart Association, Inc.

Vascular Biology

Hypoxia and Stretch Regulate Intercellular Communication in Vascular Smooth Muscle Cells Through Reactive Oxygen Species Formation

Douglas B. Cowan; Mara Jones; Lina M. Garcia; Sabrena Noria; Pedro J. del Nido; Francis X. McGowan, Jr

From the Departments of Anesthesiology, Perioperative and Pain Medicine (D.B.C., M.J., F.X.M.) and Cardiac Surgery (L.M.G., P.J.D.), Children’s Hospital Boston and Harvard Medical School, Boston, Mass, and Department of Laboratory Medicine and Pathobiology (S.N.), University of Toronto, Ontario, Canada.

Correspondence to Douglas B. Cowan, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Enders Room 1355, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. E-mail douglas.cowan{at}childrens.harvard.edu

Objective— We hypothesized that the alterations in vasomotor tone and adaptive remodeling responses that occur in the circulation because of hypoxia were dependent on changes in cell to cell communication through regulation of gap junction protein expression and function. Consequently, we studied the amount, distribution, and permeability of the principal vascular smooth muscle cell (VSMC) gap junction protein, connexin43, in rat aortic cultures exposed to oxygen partial pressures of 150 or 15 mm Hg.

Methods and Results— Immunohistochemical staining, immunoblot assays, and Northern blot analyses demonstrated that connexin43 expression was reversibly increased in hypoxic cultures. As a result, hypoxic cells exhibited greater intercellular communication as determined by fluorescence recovery after photobleaching experiments. Using a fluorogenic substrate, hypoxic VSMCs showed increased reactive oxygen species generation, which could be prevented by the glutathione peroxidase mimic ebselen and the mitochondrial complex I inhibitor rotenone but not with the redox-sensitive thiol pyrrolidine dithiocarbamate. The rise in connexin43 expression attributable to hypoxia could be attenuated by ebselen and rotenone treatment. Interestingly, the previously reported induction of connexin43 expression by tensile stretch was also contingent on oxidative activity.

Conclusions— Hypoxia and stretch increased gap junctional intercellular communication in VSMCs attributable to enhanced connexin43 expression initiated by reactive oxygen species formation.

Key Words: gap junction • reactive oxygen species • hypoxia • stretch • smooth muscle cell

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