title: Microparticle-Induced Activation of the Vascular Endothelium Requires Caveolin-1/Caveolae.
abstract: Microparticles (MPs) are small membrane fragments shed from normal as well as activated, apoptotic or injured cells. Emerging evidence implicates MPs as a causal and/or contributing factor in altering normal vascular cell phenotype through initiation of proinflammatory signal transduction events and paracrine delivery of proteins, mRNA and miRNA. However, little is known regarding the mechanism by which MPs influence these events. Caveolae are important membrane microdomains that function as centers of signal transduction and endocytosis. Here, we tested the concept that the MP-induced pro-inflammatory phenotype shift in endothelial cells (ECs) depends on caveolae. Consistent with previous reports, MP challenge activated ECs as evidenced by upregulation of intracellular adhesion molecule-1 (ICAM-1) expression. ICAM-1 upregulation was mediated by activation of NF-κB, Poly [ADP-ribose] polymerase 1 (PARP-1) and the epidermal growth factor receptor (EGFR). This response was absent in ECs lacking caveolin-1/caveolae. To test whether caveolae-mediated endocytosis, a dynamin-2 dependent process, is a feature of the proinflammatory response, EC's were pretreated with the dynamin-2 inhibitor dynasore. Similar to observations in cells lacking caveolin-1, inhibition of endocytosis significantly attenuated MPs effects including, EGFR phosphorylation, activation of NF-κB and upregulation of ICAM-1 expression. Thus, our results indicate that caveolae play a role in mediating the pro-inflammatory signaling pathways which lead to EC activation in response to MPs.
authors.affiliation: Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Andrews
authors.affiliation: Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States of America.|Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
mesh_terms: D000818:Animals; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D055786:Gene Knockout Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051242:Caveolin 1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D011065:Poly(ADP-ribose) Polymerases; D066246:ErbB Receptors