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(Circulation. 2004;110:1664-1669.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Estrogen Modulates Inflammatory Mediator Expression and Neutrophil Chemotaxis in Injured Arteries

Andrew P. Miller, MD; Wenguang Feng, MD, PhD; Dongqi Xing, MD, PhD; Nathaniel M. Weathington, BS; J. Edwin Blalock, PhD; Yiu-Fai Chen, PhD; Suzanne Oparil, MD

From the Vascular Biology and Hypertension Program (A.P.M., W.F., D.X., Y.-F.C., S.O.), Division of Cardiovascular Disease, Department of Medicine, and the Department of Physiology and Biophysics (N.M.W., J.E.B., S.O.), University of Alabama at Birmingham.

Correspondence to Andrew P. Miller, MD, University of Alabama at Birmingham, 1047 Zeigler Research Bldg, 703 19th St S, Birmingham, AL 35294-0007. E-mail apmiller{at}uab.edu

Received December 26, 2003; de novo received March 4, 2004; revision received April 20, 2004; accepted April 21, 2004.

Background— We have previously shown that estrogen (17ß-estradiol; E2) inhibits neointima formation and migration of leukocytes, particularly neutrophils, into rat carotid arteries after acute endoluminal injury. This study tested the hypothesis that E2 inhibits expression of adhesion molecules, chemokines, and proinflammatory cytokines in rat carotid arteries in the early hours after balloon injury, thus attenuating the stimulus for leukocyte entry and negatively modulating the injury response.

Methods and Results— Ovariectomized (OVX) rats were randomly assigned to treatment with E2 or vehicle (V) and subjected to balloon injury of the right carotid artery. After 2, 6, and 24 hours, rats were euthanized, and both carotid arteries were processed for real-time reverse transcription–polymerase chain reaction (2 and 24 hours), ELISA (6 hours), or neutrophil chemotaxis assay (24 hours). Expression of mRNA for adhesion molecules (P-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1), chemoattractants (cytokine-induced neutrophil chemoattractant [CINC]-2ß and monocyte chemoattractant protein [MCP]-1), and proinflammatory cytokines (interleukin [IL]-1 and IL-6) was markedly increased (2 to 5000 times) in injured arteries of OVX+V rats at 2 hours and was reduced by 24 hours. E2 significantly attenuated expression of the proinflammatory mediators (by 60% to 80%) at 2 hours. ELISA confirmed injury-induced upregulation of neutrophil and monocyte/macrophage chemoattractants (CINC-2, MCP-1) in OVX+V arteries and E2-induced inhibition of CINC-2 expression. E2 significantly (by 65%) inhibited neutrophil chemotactic activity of arterial homogenates.

Conclusions— E2 attenuates the early vascular injury response, at least in part, by negatively modulating proinflammatory mediator expression and the resultant chemotactic activity of injured vessels for neutrophils.

Key Words: restenosis • inflammation • hormones • vessels • women

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