title: Vascular smooth muscle cell proliferation depends on caveolin-1-regulated polyamine uptake.
abstract: Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof-of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis.
authors.affiliation: *Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Mario
authors.initials: M
authors.lastname: Grossi
authors.affiliation: *Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Catarina
authors.initials: C
authors.lastname: Rippe
authors.affiliation: †Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Ramasri
authors.initials: R
authors.lastname: Sathanoori
authors.affiliation: *Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
authors.affiliation: ‡Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Forte
authors.affiliation: †Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.affiliation: *Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Lo
authors.initials: L
authors.lastname: Persson
authors.affiliation: *Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hellstrand
authors.affiliation: *Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Bengt-Olof
authors.initials: BO
authors.lastname: Nilsson
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000601:surgery; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D015870:Gene Expression; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000096985:Calponins
chemical_list: D026923:Amino Acid Transport Systems, Basic; D002135:Calcium-Binding Proteins; D051242:Caveolin 1; D004247:DNA; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009955:Ornithine Decarboxylase; D011073:Polyamines; D000096985:Calponins; C051615:transgelin