(Circulation. 1997;95:555-556.)
© 1997 American Heart Association, Inc.
Articles |
Platelet-Derived Growth Factor and Arterial Response to Injury
ZymoGenetics, Inc, Seattle, Wash (C.E.H.), and the University of Washington School of Medicine, Seattle.
Correspondence to Alexander W. Clowes, MD, Department of Surgery, University of Washington School of Medicine, HSB 442, Box 356410, Seattle, WA 98195.
Key Words: Editorials • arteries • platelet-derived factors • receptors
 |
Introduction |
|---|
 Top Introduction References |
|---|
Platelet-derived growth factor (PDGF) was identified as the first human homologue of a retroviral transforming gene (c-sis).1 2 Since that initial discovery, the complexity of the PDGF system has continued to be unraveled. PDGF is a family of proteins comprising two separate gene products, PDGF-A and PDGF-B chains.3 The individual proteins are able to form the covalent dimers AA, AB, and BB. In addition to the three isoforms of PDGF, there are two receptor polypeptides called
and ß. The PDGF- receptor is able to bind both the PDGF-A and PDGF-B chains, whereas the PDGF-ß receptor binds only the PDGF-B chain. In the presence of ligand, the receptors form dimers on the cell surface so that / dimers bind all three PDGF isoforms (AA, AB, and BB), /ß dimers bind AB and BB, and ß/ß dimers bind only PDGF-BB.4 The specificity provided by the receptors dictates to which type of PDGF a cell is able to respond. Although PDGF was initially isolated from platelets, it has also been shown to be expressed by all vascular wall cells, including smooth muscle cells (SMCs), endothelial cells, and macrophages. When rats are made thrombocytopenic or are treated with a polyclonal antibody to all forms of PDGF, intimal thickening induced by balloon catheter injury is inhibited even though the first wave of proliferation in the media is not blocked.5 6 Polyclonal antibodies specific for the PDGF-B chain also are able to block intimal thickening, whereas antibodies specific for the PDGF-A chain have no effect on lesion development (C. Hart and M. Reidy, unpublished results). The infusion of PDGF-BB after a gentle denudation injury in the rat carotid artery increases intimal thickening but has little effect on intimal SMC replication.7 When taken together, these data support the conclusion that platelet factors, particularly PDGF, regulate the movement of SMCs from the media into the intima. PDGF-BB may be the critical molecule in the rat model. It is interesting to note that PDGF-A chain mRNA and polypeptide are rapidly upregulated in the media after balloon injury in the rat. Because neutralizing studies with the anti–PDGF-A chain antibody have no effect on lesion development, it remains unclear what role the PDGF-A chain plays in the artery wall.
The observations of Sirois et al8 provide additional support for the conclusion that PDGF and PDGF receptor activation are important for the injury response. Using immunohistochemical analysis, they observed that both PDGF- and PDGF-ß receptors are present in the normal artery wall. After injury, both receptor proteins are markedly upregulated. They further demonstrated that treatment of balloon-injured vessels in the rat with antisense oligonucleotides to PDGF-ß receptor significantly decreased PDGF-ß receptor expression and inhibited intimal thickening. Although these results support a critical role for PDGF, they do not determine whether the effect observed is due to inhibition of SMC migration, inhibition of SMC proliferation, or their combination. It is important for additional experiments to address this issue.
Assuming that the platelet is the primary source of PDGF, one must look at the PDGF composition of platelets. In the rat, pig, and baboon, PDGF-BB is the major isoform present9 10 ; in humans, all three PDGF isoforms are present in platelets in equal amounts.11 The receptor phenotypes of the various cells present in the artery wall also need to be considered when we are determining what potential biological activities PDGF may stimulate. There is good evidence that PDGF-ß receptor is expressed in vascular smooth muscle cells of multiple species, including rat, baboon, and human. In contrast, high levels of PDGF- receptor are expressed in the rat as demonstrated by Sirois et al,8 whereas only low-level expression has been detected in normal or injured arteries of the baboon (unpublished results). No definitive studies that address this question in humans have been published. What could we expect with PDGF- receptor blockade, and would it be similar between rats and humans, considering the differences in platelet PDGF composition? Would the blockade of PDGF receptor activation inhibit migration (as in the rat) or other cellular activities contributing to stenosis, including cell proliferation, cell death, matrix synthesis, and vascular remodeling12 13 14 15 16 ? These questions need to be answered.
Is an antisense approach going to work in humans? The question of specificity of the antisense oligonucleotides has not been resolved. Specificity of antisense treatment has always been and remains a serious concern. The observation that two separate antisense oligonucleotides to the PDGF-ß receptor decreased PDGF-ß receptor expression but did not affect PDGF- receptor expression indicates that the effect was specific for the PDGF-ß receptor. Sirois et al8 also made a concerted effort to limit nonspecific interactions by selecting sequences lacking multiple guanines. The lack of effect of PDGF-ß receptor blockade on PDGF- receptor expression indicates that the increase in expression of both of these receptors after balloon injury in the rat is not linked. One might speculate that the activation of the PDGF- receptor by platelet PDGF-BB might be a necessary precursor for PDGF- receptor upregulation.
It is not clear that the antisense oligonucleotides can be delivered readily to the lesion in humans by a luminal approach. In addition, uptake of antisense oligonucleotides in complex atherosclerotic lesions might be reduced compared with the uptake in injured normal vessels.17 Although prolonged delivery was obtained by use of a slow-release gel matrix in the rat study, such an approach is not readily applicable in humans. It is also not clear what length of time the antisense oligonucleotides need to be present for maximal effect. It is conceivable that immediate yet short-lived blockade of the initial upregulation of the PDGF-ß receptor may have long-term effects.
Supporting the concept of PDGF-ß receptor blockade for inhibiting lesion development are three studies using neutralizing PDGF-ß receptor antibodies that were reported at the Restenosis Summit VIII held in May 1996 in Cleveland, Ohio. We observed that a neutralizing mouse/human chimeric antibody to the human PDGF-ß receptor was able to significantly inhibit intimal hyperplasia in the baboon after balloon injury to the saphenous artery. Giese et al demonstrated similar efficacy in the baboon in both the carotid and brachial arteries using a murine monoclonal antibody, whereas Guzman et al demonstrated a decrease in lesion development in the rat carotid artery after balloon injury using a murine monoclonal antibody. Taken together, the observations with antisense oligonucleotides and neutralizing antibodies strongly support PDGF-ß receptor blockade as a potential therapeutic strategy for inhibiting vascular lesion formation at sites of acute injury.
We now have considerable information that platelets and platelet factors may represent good targets for pharmacology designed to interfere with intimal hyperplasia. The success of the recent coronary angioplasty trials with antibodies against platelet glycoprotein IIb/IIIa further supports this view.18 19 At what level should we intervene? It appears that there are limitations to a direct attack on the platelet because vigorous treatment can produce hemorrhage. We now have evidence that inhibition of PDGF itself, or its corresponding receptor, can limit the extent of intimal hyperplasia in animal models of vascular reconstruction. These observations suggest that a specific antagonist for PDGF may prove useful in humans, particularly because PDGF-B chain and PDGF-ß receptor can be colocalized in human coronary arteries treated with angioplasty.20
Will an antisense or blocking antibody strategy or any other strategy designed to interfere with PDGF signaling work in humans? We have as yet no test of the hypothesis that PDGF plays a critical role in the injury response in patients undergoing vascular reconstruction, although we know that the various components of the system (platelets, PDGF, and PDGF receptors) are all present at the critical sites of lesion formation. It is now time for a test of this hypothesis.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Doolittle RF, Hunkapiller MW, Hood LE, DeVare SG, Robbins KC, Aaronson SA, Antoniades HN. Simian sarcoma virus oncogene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983;221:275-277.
2. Waterfield MD, Scrace GT, Whittle N, Stroobant P, Johnsson H, Wasteson A, Westermark B, Heldin CH, Huang JS, Deuel TF. Platelet-derived growth factor is structurally related to the putative transforming protein p28-sis of simian sarcoma virus. Nature. 1983; 304:35-39.
3. Raines EW, Bowen-Pope DF, Ross R. Platelet-derived growth factor. In: Sporn MB, Roberts AB, eds. Handbook of Experimental Pharmacology: Peptide Growth Factors and Their Receptors. Heidelberg, Germany: Springer-Verlag; 1990:73-262.
4.
Seifert RA, Hart CE, Phillips PE, Forstrom JW, Ross R, Murray MJ, Bowen-Pope DF. Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. J Biol Chem. 1989;264:8771-8778.
5.
Fingerle J, Johnson R, Clowes AW, Majesky MW, Reidy MA. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci U S A. 1989;86:8412-8416.
6.
Ferns GAA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science. 1991;253:1129-1132.
7. Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW: Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992;89:507-511.
8.
Sirois MG, Simons M, Edelman ER. Antisense oligonucleotide inhibition of PDGF-ß receptor subunit expression directs suppression of intimal thickening. Circulation. 1997;95:669-676.
9.
Bowen-Pope DF, Hart CE, Seifert RA. Sera and conditioned media contain different isoforms of platelet-derived growth factor (PDGF) which bind to different classes of PDGF receptor. J Biol Chem. 1989;264:2502-2508.
10. Kraiss LW, Raines EW, Wilcox JN, Seifert RA, Barrett TB, Kirkman TR, Hart CE, Bowen-Pope DF, Ross R, Clowes AW. Regional expression of the platelet-derived growth factor and its receptors in a primate graft model of vessel wall assembly. J Clin Invest. 1993;92:338-348.
11. Hart CE, Bailey M, Curtis DA, Osborn S, Raines E, Ross R, Forstrom JW. Purification of PDGF-AB and PDGF-BB from human platelet extracts and identification of all three PDGF dimers in human platelets. Biochemistry. 1990;29:166-172.[Medline] [Order article via Infotrieve]
12. Claesson-Welsh L. Mechanism of action of platelet-derived growth factor. Int J Biochem Cell Biol. 1996;28:373-385.[Medline] [Order article via Infotrieve]
13. Molloy CJ. Novel signal transduction targets in cardiovascular disease: role of platelet-derived growth factor in vascular smooth muscle cell proliferation. Drug Dev Res. 1993;29:148-157.
14. Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest. 1995;95:2266-2274.
15.
Berk BC, Alexander RW, Brock TA, Gimbrone MA Jr, Webb RC. Vasoconstriction: a new activity for platelet-derived growth factor. Science. 1986;232:87-90.
16.
Xu JH, Clark RAF. Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol. 1996;132:239-249.
17.
Bennett MR, Schwartz SM. Antisense therapy for angioplasty restenosis: some critical considerations. Circulation. 1995;92:1981-1993.
18.
EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956-961.
19. Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody: potential implications for the effect of c7E3 Fab treatment on acute thrombosis and `clinical restenosis.' J Clin Invest. 1996;98:863-874.[Medline] [Order article via Infotrieve]
20.
Tanizawa S, Ueda M, van der Loos CM, van der Wal AC, Becker AE. Expression of platelet derived growth factor B chain and beta-receptor in human coronary arteries after percutaneous transluminal coronary angioplasty: an immunohistochemical study. Heart. 1996;75:549-556.
This article has been cited by other articles:
 |
|
 |
|
  M. Kamimura, F. Bea, T. Akizawa, H. A. Katus, J. Kreuzer, and C. Viedt Platelet-Derived Growth Factor Induces Tissue Factor Expression in Vascular Smooth Muscle Cells via Activation of Egr-1 Hypertension, December 1, 2004; 44(6): 944 - 951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Noiseux, C. H. Boucher, R. Cartier, and M. G. Sirois Bolus Endovascular PDGFR-{beta} Antisense Treatment Suppressed Intimal Hyperplasia in a Rat Carotid Injury Model Circulation, September 12, 2000; 102(11): 1330 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Davies, E. L. Owens, D. P. Mason, H. Lea, P. K. Tran, S. Vergel, S. A. Hawkins, C. E. Hart, and A. W. Clowes Effect of Platelet-Derived Growth Factor Receptor-{alpha} and -{beta} Blockade on Flow-Induced Neointimal Formation in Endothelialized Baboon Vascular Grafts Circ. Res., April 14, 2000; 86(7): 779 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fishbein, J. Waltenberger, S. Banai, L. Rabinovich, M. Chorny, A. Levitzki, A. Gazit, R. Huber, U. Mayr, S. D. Gertz, et al. Local Delivery of Platelet-Derived Growth Factor Receptor-Specific Tyrphostin Inhibits Neointimal Formation in Rats Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 667 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Heldin and B. Westermark Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor Physiol Rev, October 1, 1999; 79(4): 1283 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Waltenberger, A. Uecker, J. Kroll, H. Frank, U. Mayr, J. D. Bjorge, D. Fujita, A. Gazit, V. Hombach, A. Levitzki, et al. A Dual Inhibitor of Platelet-Derived Growth Factor {beta}-Receptor and Src Kinase Activity Potently Interferes With Motogenic and Mitogenic Responses to PDGF in Vascular Smooth Muscle Cells : A Novel Candidate for Prevention of Vascular Remodeling Circ. Res., July 9, 1999; 85(1): 12 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Hernandez-Presa, C. Bustos, M. Ortego, J. Tunon, L. Ortega, and J. Egido ACE Inhibitor Quinapril Reduces the Arterial Expression of NF-{kappa}B-Dependent Proinflammatory Factors but not of Collagen I in a Rabbit Model of Atherosclerosis Am. J. Pathol., December 1, 1998; 153(6): 1825 - 1837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Banai, Y. Wolf, G. Golomb, A. Pearle, J. Waltenberger, I. Fishbein, A. Schneider, A. Gazit, L. Perez, R. Huber, et al. PDGF-Receptor Tyrosine Kinase Blocker AG1295 Selectively Attenuates Smooth Muscle Cell Growth In Vitro and Reduces Neointimal Formation After Balloon Angioplasty in Swine Circulation, May 19, 1998; 97(19): 1960 - 1969. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Mondy, V. Lindner, J. K. Miyashiro, B. C. Berk, R. H. Dean, and R. L. Geary Platelet-Derived Growth Factor Ligand and Receptor Expression in Response to Altered Blood Flow In Vivo Circ. Res., September 19, 1997; 81(3): 320 - 327. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||