Regulation of brain endothelial cells migration and angiogenesis by P-glycoprotein/caveolin-1 interaction.
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.
Barakat
Stéphane
S
Departement de Chimie-Biochimie, Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, CP 8888, Succursale Centre-Ville, Montréal, QC, Canada.
Turcotte
Sandra
S
Demeule
Michel
M
Lachambre
Marie-Paule
MP
Régina
Anthony
A
Baggetto
Loris G
LG
Béliveau
Richard
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051242:Caveolin 1; D003524:Cyclosporins; D034741:RNA, Small Interfering; D016572:Cyclosporine; C070272:valspodar