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(Circulation. 2005;112:3644-3653.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Decreased Neurotrophin TrkB Receptor Expression Reduces Lesion Size in the Apolipoprotein E–Null Mutant Mouse

Rosemary Kraemer, PhD; Peter James Baker, MS; K. Craig Kent, MD; Yuanfen Ye, MD; Jun Ji Han, BS; Rafael Tejada, BS; Michael Silane, MD; Rita Upmacis, PhD; Ruba Deeb, PhD; Yaoxin Chen, PhD; Daniel M. Levine, PhD; Barbara Hempstead, MD, PhD

From the Department of Pathology (R.K., P.J.B., Y.Y., J.J.H., R.U., R.D.), Division of Vascular Surgery (K.C.K.), and Division of Hematology (R.T., B.H.), Department of Medicine, Weill Medical College of Cornell University; The Rogosin Institute, Rockefeller University (Y.C., D.M.L.); and Beth Israel Medical Center (M.S.), New York, NY.

Correspondence to Dr Rosemary Kraemer, Weill Medical College of Cornell University, Department of Pathology, Room A631, 1300 York Ave, New York, NY 10021. E-mail rtkraeme{at}med.cornell.edu

Received November 30, 2004; de novo received May 11, 2005; revision received September 12, 2005; accepted September 19, 2005.

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.

Methods and 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.

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