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,#
* Department of Pharmacology,
Department of Physiology,
Central Research Unit,
Department of Pathology, Faculty of Medicine,
¶ Clinic Hospital of Valencia Research Foundation, and
|| Research Foundation, University General Hospital Consortium, University of Valencia E.G., Valencia, Spain;
# Centers for Biomedical Research on Respiratory Diseases (CibeRes), Carlos III Health Institute, Spanish Ministry of Health, Spain; and
** Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
The incidence of cardiovascular diseases in premenopausal women is lower than in men or postmenopausal women. This study reports the discovery of a low grade of systemic inflammation, including monocyte adhesion to arterial endothelium, elicited by menopause or estrogen depletion. Chronic treatment with low dose of 17-β-estradiol or inhibition of the renin-angiotensin system reduced this inflammation. Using an in vitro flow chamber system with human arterial and venous endothelial cells, we found that leukocytes from healthy postmenopausal women were more adhesive to the arterial endothelium than those from premenopausal women regardless of the stimulus used on endothelial cells. Increased circulating levels of IL-8, MCP-1, RANTES, and MIP-1
and monocyte CD11b expression were also encountered in postmenopausal vs premenopausal subjects. This translational data led us to investigate the mechanisms in Sprague-Dawley rats. Using intravital microscopy, we imaged mesenteric arterioles and found significant increases in arteriolar leukocyte adhesion, cell adhesion molecule expression, and plasma levels of cytokine-induced neutrophil chemoattractant (CINC/KC), MCP-1, and MIP-1 in 1-mo ovariectomized rats. Chronic treatment of ovariectomized rats with low dose of 17-β-estradiol, losartan, both, or benazepril inhibited ovariectomy-induced arteriolar mononuclear leukocyte adhesion by 77%, 58%, 92%, and 65% respectively, partly by inhibition of cell adhesion molecule up-regulation and the increase in circulating chemokines. These results demonstrate that menopause and ovariectomy generate a low grade of systemic inflammation. Therefore, administration of low doses of estrogens or inhibition of the renin-angiotensin system, at early stages of estrogen deficiency, might prevent the systemic inflammation associated with menopause and decrease the risk of suffering further cardiovascular diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Grants SAF2005-01649, SAF2005-0669, SAF2006-01002, SAF2008-03477, and SAF2008-03113 from Comision Interministerial de Ciencia y Tecnologia, Spanish Ministry of Education and Science, FIS06/0589 and Red HERACLES (Hipertensión Esencial: Red de Análisis de Canales iónicos de la musculatura Lisa arterial y su Explotación terapéutica Sistemática) no. RD06/0009/0005, Carlos III Health Institute, Spanish Ministry of Health, and research grants from Generalitat Valenciana. M.A.-T. is primarily supported by a grant from the Spanish Ministry of Foreign Affairs, C.R. by a grant from Spanish Ministry of Education and Science, and P.J.J. by a grant from the University of Valencia.
2 M.A.-T. and C.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Maria-Jesus Sanz, Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Avenida Blasco Ibañez, 15, E-46010 Valencia, Spain. E-mail address: maria.j.sanz{at}uv.es
4 Abbreviations used in this paper: HRT, hormone replacement therapy; ACE, angiotensin-converting enzyme; Ang-II, angiotensin-II; CAM, cell adhesion molecule; CINC, cytokine-induced neutrophil chemoattractant; GRO, growth related oncogene-; OVZ, ovariectomized.
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