Regulation of brain endothelial cells migration and angiogenesis by P-glycoprotein/caveolin-1 interaction

• Published in: Biochemical and biophysical research communications Vol. 372; no. 3; pp. 440 - 446
• Main Authors: Barakat, Stéphane, Turcotte, Sandra, Demeule, Michel, Lachambre, Marie-Paule, Régina, Anthony, Baggetto, Loris G., Béliveau, Richard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2008; Elsevier
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biochemistry, Molecular Biology; Blood–brain barrier; Brain - blood supply; Caveolae; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin-1; Cell Line; Cell Movement - drug effects; Cell Movement - genetics; Cyclosporine - pharmacology; Cyclosporins - pharmacology; Dogs; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - physiology; Life Sciences; Migration; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; P-glycoprotein; Rats; RNA, Small Interfering - genetics; Tubulogenesis; Caveolin-1; BCA; P-gp; TBS; Caveolae; Migration; MACS; IP; PVDF; ECM; Endothelial cells; Blood–brain barrier; CsA; P-glycoprotein; TBS-T; ECs; Tubulogenesis; Cav; MDR; ID; MDCK
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.05.012

We have investigated the involvement of P-glycoprotein (P-gp)/caveolin-1 interaction in the regulation of brain endothelial cells (EC) migration and tubulogenesis. P-gp overexpression in MDCK-MDR cells was correlated with enhanced cell migration whereas treatment with P-gp inhibitors CsA or PSC833 reduced it. Transfection of RBE4 rat brain endothelial cells with mutated versions of MDR1, in the caveolin-1 interaction motif, decreased the interaction between P-gp and caveolin-1, enhanced P-gp transport activity and cell migration. Moreover, down-regulation of caveolin-1 in RBE4 cells by siRNA against caveolin-1 stimulated cell migration. Interestingly, the inhibition of P-gp/caveolin-1 interaction increased also EC tubulogenesis. Furthermore, decrease of P-gp expression by siRNA inhibited EC tubulogenesis. These data indicate that the level of P-gp/caveolin-1 interaction can modulate brain endothelial angiogenesis and P-gp dependent cell migration.