Upregulation of proinflammatory proteins through NF-kappaB pathway by shed membrane microparticles results in vascular hyporeactivity.
OBJECTIVE
Microparticles are membrane vesicles with procoagulant and proinflammatory properties released during cell activation, including apoptosis. The present study was designed in dissecting the effects evoked by microparticles on vascular reactivity.


RESULTS
Microparticles from either apoptotic T lymphocytic cells or from plasma of diabetic patients with vascular complications induced vascular hyporeactivity in response to vasoconstrictor agents in mouse aorta. Hyporeactivity was reversed by nitric oxide (NO) synthase plus cyclooxygenase-2 inhibitors, and associated with an increased production of vasodilatory products such as NO and prostacyclin. Microparticles induced an upregulation of proinflammatory protein expressions, inducible NO-synthase and cyclooxygenase-2, mainly in the medial layer of the vessels as evidenced by immunochemical staining. In addition, microparticles evoke NF-kappaB activation probably through the interaction with the Fas/Fas Ligand pathway. Finally, in vivo treatment of mice with lymphocyte-derived MPs induces vascular hyporeactivity, which was reversed by the combination of NO and cyclooxygenase-2 inhibitors.


CONCLUSIONS
These data provide a rationale to explain the paracrine role of microparticles as vectors of transcellular exchange of message in promoting vascular dysfunction during inflammatory diseases.
Tesse
Angela
A
Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Illkirch, France.
Martínez
M Carmen
MC
Hugel
Bénédicte
B
Chalupsky
Karel
K
Muller
Christian D
CD
Meziani
Ferhat
F
Mitolo-Chieppa
Delia
D
Freyssinet
Jean-Marie
JM
Andriantsitohaina
Ramaroson
R
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D053222:Fas Ligand Protein; D020672:I-kappa B Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D010316:Particle Size; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D051996:Transcription Factor RelA / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D014657:Vasculitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D048069:Tumor Necrosis Factors; D014662:Vasoconstrictor Agents; D019014:fas Receptor; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2