title: Accumulation of serum lipids by vascular smooth muscle cells involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter A1.
abstract: Vascular smooth muscle cells (VSMC) are present in arterial intima before atherosclerotic plaques develop and are likely to be exposed to unmodified serum lipids as they enter the vessel wall. We examined the effects of sera from mice on the morphology and function of mouse VSMC. Incubation of a mouse VSMC line (MOVAS) with sera from normocholesterolemic (C57BL/6J) or hypercholesterolemic (APOE(-/-)) mice caused concentration-dependent increases in lipid accumulation as measured by AdipoRed, with the extent of lipid uptake significantly greater with the latter sera type. Inhibition of c-Jun N-terminal kinases (SP600125), Src kinases (AG1879), and clathrin-dependent endocytosis (monodansylcadaverine) to disrupt scavenger receptor-mediated uptake of lipids had no effect on serum-induced lipid accumulation by VSMC. By contrast, inhibition of macropinocytosis with antagonists of PI-3 kinase (LY294002) and actin (cytochalasin D) markedly reduced lipid accumulation. Serum exposure reduced the expression of the ATP-binding cassette transporter A1, consistent with impaired cholesterol efflux, but had no effect on the expression of markers of VSMC differentiation. Moreover, the expression of several inflammation and foam cell markers was unchanged (CCL2, CCL5, and CD68) by mouse sera. The accumulation of unmodified serum lipids by VSMC involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter. We speculate that VSMC may play an atheroprotective role in arterial intima by acting as a "sink" for unmodified lipids.
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Building 13E, Wellington Road, Clayton, VIC, 3800, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rivera
authors.forename: Anna K
authors.initials: AK
authors.lastname: Walduck
authors.forename: Shane R
authors.initials: SR
authors.lastname: Thomas
authors.forename: Elias N
authors.initials: EN
authors.lastname: Glaros
authors.forename: Elizabeth U
authors.initials: EU
authors.lastname: Hooker
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Guida
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood; D008055:Lipids / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010873:Pinocytosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000199:Actins; D001057:Apolipoproteins E; D015415:Biomarkers; D018836:Inflammation Mediators; D008055:Lipids; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C577833:Abca1 protein, mouse