Circulation Research, Vol 75, 410-417, Copyright © 1994 by American Heart Association

ARTICLES

Does platelet-derived growth factor-A chain stimulate proliferation of arterial mesenchymal cells in human atherosclerotic plaques?

MD Rekhter and D Gordon
Department of Pathology, University of Michigan, Ann Arbor 48109-0602.

Previous studies have indicated the focal presence of growth factors and focal low levels of cell proliferation in human atherosclerotic plaques. Using human carotid plaques and an antibody to platelet- derived growth factor (PDGF)-A chain, we have begun to assess growth factor significance by spatially correlating growth factor gene expression with actual cell proliferation. Since PDGF is a mitogen for smooth muscle and related cells and since inflammatory cells (eg, macrophages) can also proliferate in these lesions, it was important to exclude inflammatory cell proliferation from this consideration. Therefore, we have used a triple immunolabeling approach, combining the above anti-PDGF-A chain antibody with an inflammatory cell cocktail (CD68+CD45 for monocyte/macrophages and lymphocytes) and adding an anti- proliferating cell nuclear antigen (PCNA) antibody to mark proliferating cells. In the carotid atherosclerotic plaques, PDGF immunostaining was distributed focally, preferentially in the fibrous cap and vascularized regions, and was present in two distinct patterns: cytoplasmic and diffuse extracellular staining. When we considered colocalization within the same cells, cytoplasmic PDGF-A staining did not appear to colocalize with inflammatory markers. PCNA nuclear staining combined with PDGF cytoplasmic staining of the same cell was detected extremely rarely. Considering colocalization within the same microscopic fields, PDGF-A staining was detected more frequently than noninflammatory PCNA positivity. Quantitative logistic regression analysis demonstrated that localization in vascularized regions and (independently) the presence of PDGF-A are good predictors of noninflammatory cell proliferation, within the same microscopic fields. Therefore, PDGF-A and other factors especially associated with vascularized regions may be involved in the regulation of mesenchymal cell proliferation in human atherosclerotic plaques.

This article has been cited by other articles:

				M.-S. Kuo, J. M. Kalbfleisch, P. Rutherford, D. Gifford-Moore, X.-d. Huang, R. Christie, K. Hui, K. Gould, and M. Rekhter Chemical analysis of atherosclerotic plaque cholesterol combined with histology of the same tissue J. Lipid Res., June 1, 2008; 49(6): 1353 - 1363. [Abstract] [Full Text] [PDF]

				I. Helantera, R. Loginov, P. Koskinen, T. Tornroth, C. Gronhagen-Riska, and I. Lautenschlager Persistent cytomegalovirus infection is associated with increased expression of TGF-{beta}1, PDGF-AA and ICAM-1 and arterial intimal thickening in kidney allografts Nephrol. Dial. Transplant., April 1, 2005; 20(4): 790 - 796. [Abstract] [Full Text] [PDF]

				N. M. Caplice, C. Panetta, T. E. Peterson, L. S. Kleppe, C. S. Mueske, G. M. Kostner, G. J. Broze Jr, and R. D. Simari Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis Blood, November 15, 2001; 98(10): 2980 - 2987. [Abstract] [Full Text] [PDF]

				D. J. Lamb, T. Y. Avades, and G. A. A. Ferns Endogenous Neutralizing Antibodies Against Platelet-Derived Growth Factor-AA Inhibit Atherogenesis in the Cholesterol-Fed Rabbit Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 997 - 1003. [Abstract] [Full Text] [PDF]

				W. J. Rogers, J. W. Prichard, Y.-L. Hu, P. R. Olson, D. H. Benckart, C. M. Kramer, D. A. Vido, and N. Reichek Characterization of Signal Properties in Atherosclerotic Plaque Components by Intravascular MRI Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1824 - 1830. [Abstract] [Full Text] [PDF]

				L. M. Taylor and L. M. Khachigian Induction of Platelet-derived Growth Factor B-chain Expression by Transforming Growth Factor-beta Involves Transactivation by Smads J. Biol. Chem., May 26, 2000; 275(22): 16709 - 16716. [Abstract] [Full Text] [PDF]

				X. Bao, C. Lu, and J. A. Frangos Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells : Role of NO, NF{kappa}B, and egr-1 Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 996 - 1003. [Abstract] [Full Text] [PDF]

				M. D. Rekhter, N. Shah, R. D. Simari, C. Work, J.-S. Kim, G. J. Nabel, E. G. Nabel, and D. Gordon Graft Permeabilization Facilitates Gene Therapy of Transplant Arteriosclerosis in a Rabbit Model Circulation, September 29, 1998; 98(13): 1335 - 1341. [Abstract] [Full Text] [PDF]

				N. M. Caplice, C. S. Mueske, L. S. Kleppe, and R. D. Simari Presence of Tissue Factor Pathway Inhibitor in Human Atherosclerotic Plaques Is Associated With Reduced Tissue Factor Activity Circulation, September 15, 1998; 98(11): 1051 - 1057. [Abstract] [Full Text] [PDF]

				N. Koyama, M. G. Kinsella, T. N. Wight, U. Hedin, and A. W. Clowes Heparan Sulfate Proteoglycans Mediate a Potent Inhibitory Signal for Migration of Vascular Smooth Muscle Cells Circ. Res., August 10, 1998; 83(3): 305 - 313. [Abstract] [Full Text] [PDF]

				G. J. Delbridge and L. M. Khachigian FGF-1–Induced Platelet-Derived Growth Factor-A Chain Gene Expression in Endothelial Cells Involves Transcriptional Activation by Early Growth Response Factor-1 Circ. Res., August 19, 1997; 81(2): 282 - 288. [Abstract] [Full Text]

				K. B. Lemstrom and P. K. Koskinen Expression and Localization of Platelet-Derived Growth Factor Ligand and Receptor Protein During Acute and Chronic Rejection of Rat Cardiac Allografts Circulation, August 19, 1997; 96(4): 1240 - 1249. [Abstract] [Full Text]

				N. A. Scott, G. D. Cipolla, C. E. Ross, B. Dunn, F. H. Martin, L. Simonet, and J. N. Wilcox Identification of a Potential Role for the Adventitia in Vascular Lesion Formation After Balloon Overstretch Injury of Porcine Coronary Arteries Circulation, June 15, 1996; 93(12): 2178 - 2187. [Abstract] [Full Text]

				C. E. Murry, T. Bartosek, C. M. Giachelli, C. E. Alpers, and S. M. Schwartz Platelet-Derived Growth Factor–A mRNA Expression in Fetal, Normal Adult, and Atherosclerotic Human Aortas : Analysis by Competitive Polymerase Chain Reaction Circulation, March 15, 1996; 93(6): 1095 - 1106. [Abstract] [Full Text]

				S. M. Schwartz, D. deBlois, and E. R. M. O'Brien The Intima : Soil for Atherosclerosis and Restenosis Circ. Res., September 1, 1995; 77(3): 445 - 465. [Full Text]

				E. Falk, P. K. Shah, and V. Fuster Coronary Plaque Disruption Circulation, August 1, 1995; 92(3): 657 - 671. [Full Text]