Decreased neurotrophin TrkB receptor expression reduces lesion size in the apolipoprotein E-null mutant mouse.
BACKGROUND
Accumulation of macrophages and smooth muscle cells in the vascular wall is critical for the development of atherosclerotic lesions. Although much is known about the factors that regulate macrophage recruitment to the vascular wall, the ability of growth factors to regulate smooth muscle cell recruitment in lesion development in vivo is unclear. Our previous studies demonstrated that neurotrophins and their receptors, the Trk receptor tyrosine kinases, are potent chemotactic factors for smooth muscle cells, and the expression of brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, is upregulated in human atherosclerotic lesions.


RESULTS
TrkB(+/-) mice on a 129/B6 background were backcrossed to apolipoprotein E (ApoE)-null (ApoE(-/-)) mice on the C57Bl/6 background for 6 to 8 generations. Immunohistochemical analysis demonstrated BDNF immunoreactivity in areas of macrophage and smooth muscle cell infiltration, whereas TrkB immunoreactivity was predominant in areas of neointimal smooth muscle cells. Moreover, haplodeficient expression of TrkB in ApoE(-/-) mice was associated with a 30% to 40% reduction in lesion size compared with ApoE(-/-) mice with normal expression of TrkB and a 45% decrease in smooth muscle cell accumulation in the lesions. Finally, reconstitution with bone marrow from ApoE(-/-) mice with normal TrkB expression did not restore lesion development in TrKB(+/-)/ApoE(-/-) mice.


CONCLUSIONS
These results suggest that TrkB expression on smooth muscle cells contributes to lesion development in the cholesterol-fed ApoE-null mutant mouse. These data demonstrate, for the first time, a role for the neurotrophin TrkB receptor in atherosclerotic lesion development.
Kraemer
Rosemary
R
Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021, USA. rtkraeme@med.cornell.edu
Baker
Peter James
PJ
Kent
K Craig
KC
Ye
Yuanfen
Y
Han
Jun Ji
JJ
Tejada
Rafael
R
Silane
Michael
M
Upmacis
Rita
R
Deeb
Ruba
R
Chen
Yaoxin
Y
Levine
Daniel M
DM
Hempstead
Barbara
B
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D002633:Chemotaxis; D002784:Cholesterol / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000502:physiology; D008264:Macrophages / Q000737:chemistry / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000502:physiology; D020813:Receptor, trkB / Q000235:genetics* / Q000502:physiology*
D001057:Apolipoproteins E; D019208:Brain-Derived Neurotrophic Factor; D002784:Cholesterol; D020813:Receptor, trkB