Abstract
Vascular smooth muscle cell (SMC) proliferation and migration are important events in the development of atherosclerosis. The low-density lipoprotein receptor-related protein (LRP1) mediates suppression of SMC migration induced by platelet-derived growth factor (PDGF). Here we show that LRP1 forms a complex with the PDGF receptor (PDGFR). Inactivation of LRP1 in vascular SMCs of mice causes PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, SMC proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis. The development of these abnormalities was reduced by treatment with Gleevec, an inhibitor of PDGF signaling. Thus, LRP1 has a pivotal role in protecting vascular wall integrity and preventing atherosclerosis by controlling PDGFR activation.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Aorta / cytology
-
Aorta / metabolism
-
Aorta / pathology*
-
Arteriosclerosis / pathology*
-
Arteriosclerosis / physiopathology
-
Arteriosclerosis / prevention & control*
-
Becaplermin
-
Benzamides
-
Cattle
-
Cell Division
-
Cell Line
-
Cholesterol, Dietary / administration & dosage
-
Diet, Atherogenic
-
Elastin / analysis
-
Enzyme Inhibitors / pharmacology
-
Imatinib Mesylate
-
Ligands
-
Low Density Lipoprotein Receptor-Related Protein-1 / genetics
-
Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
-
Low Density Lipoprotein Receptor-Related Protein-1 / physiology*
-
Mesenteric Arteries / cytology
-
Mesenteric Arteries / pathology
-
Mice
-
Mice, Knockout
-
Mice, Transgenic
-
Muscle, Smooth, Vascular / cytology
-
Muscle, Smooth, Vascular / metabolism*
-
Muscle, Smooth, Vascular / pathology
-
Myocytes, Smooth Muscle / metabolism*
-
Myocytes, Smooth Muscle / physiology
-
Phosphorylation
-
Piperazines / pharmacology
-
Platelet-Derived Growth Factor / metabolism
-
Platelet-Derived Growth Factor / pharmacology
-
Proto-Oncogene Proteins c-sis
-
Pyrimidines / pharmacology
-
Receptor, Platelet-Derived Growth Factor beta / metabolism
-
Signal Transduction
Substances
-
Benzamides
-
Cholesterol, Dietary
-
Enzyme Inhibitors
-
Ligands
-
Low Density Lipoprotein Receptor-Related Protein-1
-
Piperazines
-
Platelet-Derived Growth Factor
-
Proto-Oncogene Proteins c-sis
-
Pyrimidines
-
Becaplermin
-
Imatinib Mesylate
-
Elastin
-
Receptor, Platelet-Derived Growth Factor beta