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(American Journal of Pathology. 2002;161:1395-1407.)
© 2002 American Society for Investigative Pathology

Regular Articles

Blockade of Platelet-Derived Growth Factor or Its Receptors Transiently Delays but Does Not Prevent Fibrous Cap Formation in ApoE Null Mice

Koichi Kozaki^*, Wolfgang E. Kaminski^*, Jingjing Tang^*, Stan Hollenbach, Per Lindahl, Carol Sullivan, Jin-Chen Yu, Keith Abe, Paul J. Martin, Russell Ross^*, Christer Betsholtz, Neill A. Giese and Elaine W. Raines^*

From the Department of Pathology,^* University of Washington School of Medicine, Seattle, Washington; COR Therapeutics, Inc., South San Francisco, California; the Department of Medical Biochemistry, University of Göteborg, Göteborg, Sweden; and the Fred Hutchinson Cancer Research Center, Seattle, Washington

Platelet-derived growth factor (PDGF) is a potent stimulant of smooth muscle cell migration and proliferation in culture. To test the role of PDGF in the accumulation of smooth muscle cells in vivo, we evaluated ApoE -/- mice that develop complex lesions of atherosclerosis. Fetal liver cells from PDGF-B-deficient embryos were used to replace the circulating cells of lethally irradiated ApoE -/- mice. One month after transplant, all monocytes in PDGF-B -/- chimeras are of donor origin (lack PDGF), and no PDGF-BB is detected in circulating platelets, primary sources of PDGF in lesions. Although lesion volumes are comparable in the PDGF-B +/+ and -/- chimeras at 35 weeks, lesions in PDGF-B -/- chimeras contain mostly macrophages, appear less mature, and have a reduced frequency of fibrous cap formation as compared with PDGF-B +/+ chimeras. However, after 45 weeks, smooth muscle cell accumulation in fibrous caps is indistinguishable in the two groups. Comparison of elicited peritoneal macrophages by RNase protection assay shows an altered cytokine and cytokine receptor profile in PDGF-B -/- chimeras. ApoE -/- mice were also treated for up to 50 weeks with a PDGF receptor antagonist that blocks all three PDGF receptor dimers. Blockade of the PDGF receptors similarly delays, but does not prevent, accumulation of smooth muscle and fibrous cap formation. Thus, elimination of PDGF-B from circulating cells or blockade of PDGF receptors does not appear sufficient to prevent smooth muscle accumulation in advanced lesions of atherosclerosis.

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