Early and Late-Onset Effect of Chronic Stress on Vascular Function in Mice: A Possible Model of the Impact of Depression on Vascular Disease in Aging Elsa Isingrini, Ph.D., Catherine Belzung, Ph.D., Alexandre d’Audiffret, M.D., Vincent Camus, Ph.D. Depression is recognized as a predictor of increased cardiac morbidity and mortality. In addition, depressed patients exhibit an increase in the serum markers of endothe- lial dysfunction and platelet activation involved in the cascade of events leading to atherosclerosis. The purpose of this study was to determine the early and late-onset expression of various vascular markers in a rodent model of depression. Male DBA (an inbred strain of mice)/2J mice were exposed to either 7 weeks of controlled liv- ing conditions or unpredictable chronic mild stress (UCMS), and subsequently given daily fluoxetine (10 mg/kg) or NaCl (9%) during the last 5 weeks of the experiment. Depressive-like behavior was evaluated by using motivational and self-care behavior, including the assessment of the animal’s coat state and grooming behavior. Enzyme- linked immunoassay was used to quantify matrix metalloproteinase-9 (MMP-9), vas- cular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1) expression either immediately after the end of the UCMS procedure (short term condition) or 10 months later (long-term con- dition). Results indicate that 1) UCMS procedure induces a short-term depressive-like behavior in mice, defined as coat state deterioration, an effect that is prevented by fluoxetine treatment; 2) UCMS procedure has no effect on the short-term expression of the studied markers; however, UCMS increases expression of plasminogen activator inhibitor-1 only in the long-term group; 3) fluoxetine treatment is unable to counter- act this UCMS-induced change; 4) aging induces behavioral perturbation, defined as a decrease in grooming motivation, and an increase of all the vascular markers in both control and UCMS groups and 5) pretreatment with fluoxetine has no protective effects on aging-induced behavioral and vascular alterations. Thus, in this model of depression-like behavior, UCMS appears to induce late-onset physiological changes, Received October 21, 2009; revised June 5, 2010; accepted July 23, 2010. From the UMRS INSERM U930, CNRS ERL 3106, 37000 Tours, France (EI, CB, VC); Universit´ e Franc ¸ois–Rabelais, 37200 Tours, France (EI, CB, VC); Center for interdisciplinary research in cardiovascular Sciences, West Virginia University, Morgantown, (AA); Department of Surgery, Division of Vascular and Endovascular Surgery, West Virginia University, Morgantown (AA); and Clinique Psychiatrique Universitaire, CHRU de Tours, 37044 Tours, France (VC). Send correspondence and reprint requests to Isingrini Elsa, M.S.C., INSERM U930, Team 4 (Affective disorders), Universit´ e Franc ¸ois Rabelais de Tours, Parc Grandmont, Batiment O, 37041 Tours Cedex 01. e-mail: Isingrini.elsa@voila.fr c  2011 American Association for Geriatric Psychiatry DOI: 10.1097/JGP.0b013e318202bc42 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Am J Geriatr Psychiatry 19:4, April 2011 335