Biology of Cytokines

Kidney International (1997) 51, 1361–1369; doi:10.1038/ki.1997.186

Platelet-derived growth factor: A key regulator of connective tissue cells in embryogenesis and pathogenesis

Christer Betsholtz and Elaine W Raines

  1. Department of Medical Biochemistry, University of Güteborg, Güteborg, Sweden
  2. Department of Pathology, University of Washington, Seattle, Washington, USA

Correspondence: Elaine W Raines MD, Department of Pathology, Box 357470, University of Washington, Seattle, Washington 98915, USA. E-mail: ewraines@u.washington.edu

Top

Abstract

Platelet-derived growth factor: A key regulator of connective tissue cells in embryogenesis and pathogenesis. Studies of PDGF-A, PDGF-B and PDGF receptor-beta knock-out mice have revealed critical functions for the PDGF-PDGF receptor signaling systems in the ontogeny of connective tissue cells: the mesangial cells of kidney glomeruli and the alveolar smooth muscle cells (SMC) of the lung. The phenotypes of the PDGF mutant mice have also shed light on the identity and functions of these cell types, as well as revealed analogies suggesting that common morphogenetic principles have evolved for use in different organs, involving related growth factors and cell types. Although the lethality of PDGF knock-out mice has not allowed an investigation of the role of PDGF in SMC of the vessel wall, regulation of PDGF and its receptors in adult vessels following injury is consistent with a role for PDGF in the fibroproliferative response in the intima that occurs as part of the pathogenesis of atherosclerosis. PDGF modulation of connective tissue synthesis may thus be critical to connective tissue phenotype and proliferation in both embryogenesis and pathogenesis.

Top

References

  1. Heldin C-H: Structural and functional studies of platelet-derived growth factor. EMBO J 11:4251–4259, 1992 | PubMed | ISI | ChemPort |
  2. Claesson-Welsh L: PDGF receptors: Structure and mechanism of action, in Cytokines (vol 5): Biology of Platelet-Derived Growth Factor, edited by Westermark B, Sorg C, Basel, S Karger AG, 1993, pp 31–43 | Article |
  3. Westermark B, Sorg C: Cytokines (vol 5):Biology of Platelet-Derived Growth Factor, Basel, S Karger AG, 1993, pp 1–167
  4. Raines EW, Bowen-Pope DF, Ross R: Platelet-derived growth factor, in Handbook of Experimental Pharmacology: Peptide Growth Factors and their Receptors I (vol. 95/I), edited by Sporn MB, Roberts AB, New York, Springer-Verlag, 1990, pp 173–262
  5. Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C: Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8:1875–1887, 1994 | PubMed | ISI | ChemPort |
  6. Soriano P: Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev 8:1888–1896, 1994 | PubMed | ISI | ChemPort |
  7. Boström H, Willetts K, Pekny M, Levéen P, Lindahl P, Hedstrand H, Pekna M, Hellström M, Gebre-Medhin S, Schalling M, Nilsson M, Kurland S, Törnell J, Heath JK, Betsholtz C: PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85:863–873, 1996 | Article | PubMed | ISI | ChemPort |
  8. Capecchi MR: Altering the genome by homologous recombination. Science 244:1288–1290, 1989 | Article | PubMed | ISI | ChemPort |
  9. Olson EN, Arnold H-H, Rigby PWJ, Wold BJ: Know your neighbors: Three phenotypes in null mutants of the myogenic bHLH gene MRF4. Cell 85:1–4, 1996 | Article | PubMed | ISI | ChemPort |
  10. Ross R, Masuda J, Raines EW, Gown AM, Katsuda S, Sasahara M, Malden LT, Masuko H, Sato H: Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science 248:1009–1012, 1990 | PubMed | ISI | ChemPort |
  11. 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 92:338–348, 1993
  12. Raines EW, Ross R: Platelet-derived growth factor in vivo, in Cytokines (vol 5):Biology of Platelet-Derived Growth Factor, edited by Westermark B, Sorg C, Basel, S Karger AG, 1993, pp 74–114
  13. Ferns GAA, Raines EW, Sprugel KH, Motani A, Reidy MA, Ross R: Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 253:1129–1132, 1991 | PubMed | ISI | ChemPort |
  14. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R: Apo E-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133–140, 1994 | PubMed | ISI | ChemPort |
  15. Bowen-Pope DF, Van Koppen A, Schatteman G: Is PDGF really important? Testing the hypotheses. Trends Genet 7:413–418, 1991 | Article |
  16. Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJM, Orkin SH: Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MDGF in megakaryocyte development. Cell 81:695–704, 1995 | Article | PubMed | ISI | ChemPort |
  17. Gurney A, Carver-Moore K, Sauvage FJ, Moore MW: Thrombocytopenia in c-mpl-deficient mice. Science 265:1445–1447, 1994 | Article | PubMed | ISI | ChemPort |
  18. Rappolee DA, Brenner CA, Schultz R, Mark D, Werb Z: Developmental expression of PDGF, TGF-alpha, and TGF-beta genes in preimplantation mouse embryos. Science 241:1823–1825, 1988 | PubMed | ISI | ChemPort |
  19. Palmieri S, Payne J, Stiles CD, Biggers JD, Mercola M: Expression of mouse PDGF-A and PDGF alpha-receptor genes during pre-and post-implantation development: Evidence for a developmental shift from an autocrine to a paracrine mode of action. Mech Dev 39:181–191, 1992 | Article |
  20. Mercola M, Melton DA, Stiles CD: Platelet-derived growth factor A chain is maternally encoded in Xenopus embryos. Science 241:1223–1225, 1988 | PubMed | ISI | ChemPort |
  21. Orr-Urtreger A, Lonai P: Platelet-derived growth factor-A and its receptor are expressed in separate but adjacent cell layers of the mouse embryo. Development 115:1045–1058, 1992 | PubMed | ChemPort |
  22. Schatteman GC, Morrison-Graham K, Van Koppen A, Weston JA, Bowen-Pope DF: Regulation and role of PDGF receptor alpha-subunit expression during embryogenesis. Development 115:123–131, 1992 | PubMed | ISI | ChemPort |
  23. Schlöndorff D: The glomerular mesangial cell: An expanding role for a specialized pericyte. FASEB J 1:272–279, 1987 | PubMed | ISI | ChemPort |
  24. Kapanchi Y, Assimacopoulos A, Irle C, Zwahlen A, Gabbiani G: Contractile interstitial cells in pulmonary alveolar septa: A possible regulator of ventilation/perfusion ratio? J Cell Biol 60:375–392, 1974 | Article |
  25. Ross R: The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 362:801–809, 1993 | Article | PubMed | ISI | ChemPort |
  26. Burke JM, Ross R: Synthesis of connective tissue macromolecules by smooth muscle. Int Rev Connect Tissue Res 8:119–157, 1979
  27. Fingerle J, Au YPT, Clowes SW, Reidy MA: Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis 10:1082–1087, 1990
  28. Jackson CL, Raines EW, Ross R, Reidy MA: Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscl Thromb 13:1218–1226, 1993
  29. Fellström B, Klareskog L, Heldin C-H, Larsson E, Rönnstrand L, Terracio L, Tufveson G, Wahlberg J, Rubin K: Platelet-derived growth factor receptors in the kidney-Upregulated expression in inflammation. Kidney Int 36:1099–1102, 1989 | PubMed | ISI | ChemPort |
  30. Iida H, Seifert R, Alpers CE, Gronwald RGK, Phillips PE, Pritzl P, Gordon K, Gown AM, Ross R, Bowen-Pope DF, Johnson RJ: Platelet-derived growth factor (PDGF) and PDGF receptors are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci USA 88:6560–6564, 1991 | Article | PubMed | ChemPort |
  31. Alpers CE, Seifert RA, Hudkins KL, Johnson RJ, Bowen-Pope DF: PDGF-receptor localizes to mesangial, parietal epithelial, and interstitial cells in human and primate kidneys. Kidney Int 43:286–294, 1993 | Article | PubMed | ISI | ChemPort |
  32. Johnson RJ, Raines EW, Floege J, Yoshimura A, Pritzl P, Alpers CE, Ross R: Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 175:1413–1416, 1992 | Article | PubMed | ISI | ChemPort |
  33. Martinet Y, Rom WN, Grotendorst GR, Martin GR, Crystal RG: Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med 317:202–209, 1987 | PubMed | ChemPort |
  34. Nagaoka I, Trapnell BC, Crystal RG: Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis. Clin Invest 85:2023–2027, 1990
  35. Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, Selman M: Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 86:1055–1064, 1990 | PubMed | ISI | ChemPort |
  36. Jawien AD, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW: Platelet-derived growth factor (PDGF) promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest 89:507–511, 1992 | PubMed | ISI | ChemPort |
  37. Bendeck MP, Regenass S, Tom WD, Giachelli CM, Schwartz SM, Hart C, Reidy MA: Differential expression of alpha1 type VIII collagen in injured platelet-derived growth factor-BB-stimulated rat carotid arteries. Circ Res 79:524–531, 1996
  38. Floege J, Eng E, Young BA, Alpers CE, Barrett TB, Bowen-Pope DF, Johnson RJ: Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats. J Clin Invest 92:2952–2962, 1993 | PubMed | ISI | ChemPort |
  39. Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R: Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of cdk2 inhibitors. Cell 87:1069–1078, 1996 | Article | PubMed | ISI | ChemPort |
  40. Thyberg J, Hedin U, Sjolund M, Palmberg L, Bottger BA: Regulation of differentiated properties and proliferation of arterial smooth muscle cells. Artenosclerosis 10:966–990, 1990
  41. Darby I, Gabbiani G: alpha-Smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 63:21–29, 1990 | PubMed | ISI | ChemPort |
  42. Xu J, Clark RA: Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol 132:239–249, 1996 | Article | PubMed | ISI | ChemPort |
  43. Rubin E, Farber JL: Pathology. Philadelphia, JB Lippincott Company, 1988
  44. Muley T, Wiebel M, Schultz V, Ebert W: Elastinolytic activity of alveolar macrophages in smoking-associated pulmonary emphysema. Clin Invest 72:269–276, 1994 | Article |

Extra navigation

.
ADVERTISEMENT