Published Online
on March 15, 2004

A more recent version of this article appeared on April 6, 2004

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Submitted on February 5, 2003
Revised on November 27, 2003
Accepted on December 10, 2003

Shed Membrane Particles From T Lymphocytes Impair Endothelial Function and Regulate Endothelial Protein Expression

Sophie Martin PhD, Angela Tesse PhD, Bénédicte Hugel PhD, M. Carmen Martínez PhD, Olivier Morel MD, Jean-Marie Freyssinet PhD, and Ramaroson Andriantsitohaina PhD^*

From Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, Illkirch, France (S.M., A.T., R.A.); Institut d’Hématologie et d’Immunologie, ULP, Strasbourg, France; and Unité 143 INSERM, Hôpital de Bicêtre, France (B.H., M.C.M., O.M., J.-M.F.).

^* To whom correspondence should be addressed. E-mail: nain{at}pharma.u-strasbg.fr.

Background--Microparticles (MPs) are membrane vesicles with procoagulant and proinflammatory properties released during cell activation. The present study was designed to dissect the effects evoked by T lymphocyte-derived MPs on vascular function.

Methods and Results--MPs were produced by treatment of the human lymphoid CEM T cell line with actinomycin D or phytohemagglutinin. Incubation of mouse aortic rings with 30 nmol/L MPs resulted in a time-dependent impairment of acetylcholine-induced relaxation of precontracted vessels, with a maximal reduction after 24 hours. MPs also impaired shear stress-induced dilatation of mouse small mesenteric arteries by affecting the nitric oxide (NO) and prostacyclin but not the endothelium-derived hyperpolarizing factor components of the response. However, neither alteration of calcium signaling in response to agonists nor reduction of cyclooxygenase-1 expression accounted for the impairment of the NO and prostacyclin components of the endothelial response. The effect of MPs was rather because of a decrease in expression of endothelial NO synthase and an overexpression of caveolin-1. Furthermore, lymphocyte-derived MPs from diabetic patients or in vivo circulating MPs from either diabetic or HIV-infected patients reduced endothelial NO synthase expression. Finally, the effects of MPs on endothelial cells were not driven through CD11a/CD18 adhesion molecules or the Fas/FasL pathway.

Conclusions--MPs from T cells induce endothelial dysfunction in both conductance and resistance arteries by alteration of NO and prostacyclin pathways. MPs regulate protein expression for endothelial NO synthase and caveolin-1. These data contribute to a better understanding of the deleterious effects of enhanced circulating MPs observed in disorders with cardiovascular or immune complications.

Key words: endothelium • lymphocytes • nitric oxide • prostaglandin • cardiovascular diseases

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