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PMID: 12368212 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Blockade of platelet-derived growth factor or its receptors transiently delays but does not prevent fibrous cap formation in ApoE null mice.

The American journal of pathology ·Vol. 161 ·No. 4 ·2002-10-00 ·Pages 1395-407

Kozaki K, Kaminski WE, Tang J, Hollenbach S, Lindahl P, Sullivan C, Yu JC, Abe K, Martin PJ, Ross R, Betsholtz C, Giese NA, Raines EW

Abstract

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.

MeSH Terms
Animals Apolipoproteins E/deficiency,genetics,physiology Arteriosclerosis/genetics,pathology,prevention & control Becaplermin Blood Platelets/drug effects,physiology Mice Mice, Knockout Piperazines/pharmacology Platelet-Derived Growth Factor/antagonists & inhibitors,deficiency,genetics,physiology Polymerase Chain Reaction Proto-Oncogene Proteins c-sis Quinazolines/pharmacology Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
Chemicals
Apolipoproteins E CT52923 Piperazines Platelet-Derived Growth Factor Proto-Oncogene Proteins c-sis Quinazolines Becaplermin Receptors, Platelet-Derived Growth Factor
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Kozaki Koichi
Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
Kaminski Wolfgang E
Tang Jingjing
Hollenbach Stan
Lindahl Per
Sullivan Carol
Yu Jin-Chen
Abe Keith
Martin Paul J
Ross Russell
Betsholtz Christer
Giese Neill A
Raines Elaine W
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)64415-X
Published
2002-10-00
Pages
1395-407
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1867295
Subset
IM
Grants
NHLBI NIH HHS · P01 HL018645 · United States
NHLBI NIH HHS · HL18645 · United States
NHLBI NIH HHS · HL07828 · United States
NHLBI NIH HHS · T32 HL007828 · United States
NHLBI NIH HHS · HL55257 · United States
External Links
PubMed source DOI: 10.1016/S0002-9440(10)64415-X PMC Full Text View journal details
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