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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jun 20;92(13):5920–5924. doi: 10.1073/pnas.92.13.5920

Platelet-derived growth factor BB induces functional vascular anastomoses in vivo.

D M Brown 1, S P Hong 1, C L Farrell 1, G F Pierce 1, R K Khouri 1
PMCID: PMC41613  PMID: 7597054

Abstract

Neovascularization that generates collateral blood flow can limit the extent of tissue damage after acute ischemia caused by occlusion of the primary blood supply. The neovascular response stimulated by the BB homodimeric form of recombinant platelet-derived growth factor (PDGF-BB) was evaluated for its capacity to protect tissue from necrosis in a rat skin flap model of acutely induced ischemia. Complete survival of the tissue ensued, when the original nutritive blood supply was occluded, as early as 5 days after local PDGF-BB application, and the presence of a patent vasculature was evident compared to control flaps. To further evaluate the vascular regenerative response, PDGF-BB was injected into the muscle/connective tissue bed between the separated ends of a divided femoral artery in rats. A patent new vessel that functionally reconnected the ends of the divided artery within the original 3- to 4-mm gap was regenerated 3 weeks later in all PDGF-BB-treated limbs. In contrast, none of the paired control limbs, which received vehicle with an inactive variant of PDGF-BB, had vessel regrowth (P < 0.001). The absence of a sustained inflammatory response and granulation tissue suggests locally delivered PDGF-BB may directly stimulate the angiogenic phenotype in endothelial cells. These findings indicate that PDGF-BB can generate functional new blood vessels and nonsurgically anastomose severed vessels in vivo. This study supports the possibility of a therapeutic modality for the salvage of ischemic tissue through exogenous cytokine-induced vascular reconnection.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baffour R., Berman J., Garb J. L., Rhee S. W., Kaufman J., Friedmann P. Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose-response effect of basic fibroblast growth factor. J Vasc Surg. 1992 Aug;16(2):181–191. [PubMed] [Google Scholar]
  2. Banai S., Jaklitsch M. T., Shou M., Lazarous D. F., Scheinowitz M., Biro S., Epstein S. E., Unger E. F. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation. 1994 May;89(5):2183–2189. doi: 10.1161/01.cir.89.5.2183. [DOI] [PubMed] [Google Scholar]
  3. Battegay E. J., Rupp J., Iruela-Arispe L., Sage E. H., Pech M. PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF beta-receptors. J Cell Biol. 1994 May;125(4):917–928. doi: 10.1083/jcb.125.4.917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beitz J. G., Kim I. S., Calabresi P., Frackelton A. R., Jr Human microvascular endothelial cells express receptors for platelet-derived growth factor. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):2021–2025. doi: 10.1073/pnas.88.5.2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Claesson-Welsh L., Eriksson A., Westermark B., Heldin C. H. cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4917–4921. doi: 10.1073/pnas.86.13.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Collins T., Ginsburg D., Boss J. M., Orkin S. H., Pober J. S. Cultured human endothelial cells express platelet-derived growth factor B chain: cDNA cloning and structural analysis. Nature. 1985 Aug 22;316(6030):748–750. doi: 10.1038/316748a0. [DOI] [PubMed] [Google Scholar]
  7. Connolly D. T. Vascular permeability factor: a unique regulator of blood vessel function. J Cell Biochem. 1991 Nov;47(3):219–223. doi: 10.1002/jcb.240470306. [DOI] [PubMed] [Google Scholar]
  8. D'Amore P. A., Smith S. R. Growth factor effects on cells of the vascular wall: a survey. Growth Factors. 1993;8(1):61–75. doi: 10.3109/08977199309029135. [DOI] [PubMed] [Google Scholar]
  9. Deuel T. F., Kawahara R. S., Mustoe T. A., Pierce A. F. Growth factors and wound healing: platelet-derived growth factor as a model cytokine. Annu Rev Med. 1991;42:567–584. doi: 10.1146/annurev.me.42.020191.003031. [DOI] [PubMed] [Google Scholar]
  10. DiCorleto P. E., Bowen-Pope D. F. Cultured endothelial cells produce a platelet-derived growth factor-like protein. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1919–1923. doi: 10.1073/pnas.80.7.1919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ferns G. A., Raines E. W., Sprugel K. H., Motani A. S., Reidy M. A., Ross R. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science. 1991 Sep 6;253(5024):1129–1132. doi: 10.1126/science.1653454. [DOI] [PubMed] [Google Scholar]
  12. Ferrara N., Houck K. A., Jakeman L. B., Winer J., Leung D. W. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991 Nov;47(3):211–218. doi: 10.1002/jcb.240470305. [DOI] [PubMed] [Google Scholar]
  13. Finkenzeller G., Marmé D., Weich H. A., Hug H. Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res. 1992 Sep 1;52(17):4821–4823. [PubMed] [Google Scholar]
  14. Folkman J., Shing Y. Control of angiogenesis by heparin and other sulfated polysaccharides. Adv Exp Med Biol. 1992;313:355–364. doi: 10.1007/978-1-4899-2444-5_34. [DOI] [PubMed] [Google Scholar]
  15. Forsberg K., Valyi-Nagy I., Heldin C. H., Herlyn M., Westermark B. Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):393–397. doi: 10.1073/pnas.90.2.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fouser L., Iruela-Arispe L., Bornstein P., Sage E. H. Transcriptional activity of the alpha 1(I)-collagen promoter is correlated with the formation of capillary-like structures by endothelial cells in vitro. J Biol Chem. 1991 Sep 25;266(27):18345–18351. [PubMed] [Google Scholar]
  17. Gatti J. E., LaRossa D., Brousseau D. A., Silverman D. G. Assessment of neovascularization and timing of flap division. Plast Reconstr Surg. 1984 Mar;73(3):396–402. doi: 10.1097/00006534-198403000-00010. [DOI] [PubMed] [Google Scholar]
  18. Golden M. A., Au Y. P., Kirkman T. R., Wilcox J. N., Raines E. W., Ross R., Clowes A. W. Platelet-derived growth factor activity and mRNA expression in healing vascular grafts in baboons. Association in vivo of platelet-derived growth factor mRNA and protein with cellular proliferation. J Clin Invest. 1991 Feb;87(2):406–414. doi: 10.1172/JCI115011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Graham B. H., Walton R. L., Elings V. B., Lewis F. R. Surface quantification of injected fluorescein as a predictor of flap viability. Plast Reconstr Surg. 1983 Jun;71(6):826–833. doi: 10.1097/00006534-198306000-00016. [DOI] [PubMed] [Google Scholar]
  20. Gregg D. E. The natural history of coronary collateral development. Circ Res. 1974 Sep;35(3):335–344. doi: 10.1161/01.res.35.3.335. [DOI] [PubMed] [Google Scholar]
  21. Hermansson M., Nistér M., Betsholtz C., Heldin C. H., Westermark B., Funa K. Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7748–7752. doi: 10.1073/pnas.85.20.7748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Holmgren L., Glaser A., Pfeifer-Ohlsson S., Ohlsson R. Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression. Development. 1991 Nov;113(3):749–754. doi: 10.1242/dev.113.3.749. [DOI] [PubMed] [Google Scholar]
  23. Jaye M., McConathy E., Drohan W., Tong B., Deuel T., Maciag T. Modulation of the sis gene transcript during endothelial cell differentiation in vitro. Science. 1985 May 17;228(4701):882–885. doi: 10.1126/science.3890179. [DOI] [PubMed] [Google Scholar]
  24. Kavanaugh W. M., Harsh G. R., 4th, Starksen N. F., Rocco C. M., Williams L. T. Transcriptional regulation of the A and B chain genes of platelet-derived growth factor in microvascular endothelial cells. J Biol Chem. 1988 Jun 15;263(17):8470–8472. [PubMed] [Google Scholar]
  25. Kelly J. L., Sánchez A., Brown G. S., Chesterman C. N., Sleigh M. J. Accumulation of PDGF B and cell-binding forms of PDGF A in the extracellular matrix. J Cell Biol. 1993 Jun;121(5):1153–1163. doi: 10.1083/jcb.121.5.1153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Khouri R. K., Hong S. P., Deune E. G., Tarpley J. E., Song S. Z., Serdar C. M., Pierce G. F. De novo generation of permanent neovascularized soft tissue appendages by platelet-derived growth factor. J Clin Invest. 1994 Nov;94(5):1757–1763. doi: 10.1172/JCI117523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Khouri R. K., Koudsi B., Deune E. G., Hong S. P., Ozbek M. R., Serdar C. M., Song S. Z., Pierce G. F. Tissue generation with growth factors. Surgery. 1993 Aug;114(2):374–380. [PubMed] [Google Scholar]
  28. Klagsbrun M., D'Amore P. A. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217–239. doi: 10.1146/annurev.ph.53.030191.001245. [DOI] [PubMed] [Google Scholar]
  29. Knighton D. R., Hunt T. K., Scheuenstuhl H., Halliday B. J., Werb Z., Banda M. J. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science. 1983 Sep 23;221(4617):1283–1285. doi: 10.1126/science.6612342. [DOI] [PubMed] [Google Scholar]
  30. Knighton D. R., Silver I. A., Hunt T. K. Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration. Surgery. 1981 Aug;90(2):262–270. [PubMed] [Google Scholar]
  31. Kohler N., Lipton A. Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res. 1974 Aug;87(2):297–301. doi: 10.1016/0014-4827(74)90484-4. [DOI] [PubMed] [Google Scholar]
  32. Kourembanas S., Hannan R. L., Faller D. V. Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest. 1990 Aug;86(2):670–674. doi: 10.1172/JCI114759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kraiss L. W., Raines E. W., Wilcox J. N., Seifert R. A., Barrett T. B., Kirkman T. R., Hart C. E., Bowen-Pope D. F., Ross R., Clowes A. W. Regional expression of the platelet-derived growth factor and its receptors in a primate graft model of vessel wall assembly. J Clin Invest. 1993 Jul;92(1):338–348. doi: 10.1172/JCI116572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Majesky M. W., Reidy M. A., Bowen-Pope D. F., Hart C. E., Wilcox J. N., Schwartz S. M. PDGF ligand and receptor gene expression during repair of arterial injury. J Cell Biol. 1990 Nov;111(5 Pt 1):2149–2158. doi: 10.1083/jcb.111.5.2149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Marx M., Perlmutter R. A., Madri J. A. Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis. J Clin Invest. 1994 Jan;93(1):131–139. doi: 10.1172/JCI116936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Matsui T., Heidaran M., Miki T., Popescu N., La Rochelle W., Kraus M., Pierce J., Aaronson S. Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science. 1989 Feb 10;243(4892):800–804. doi: 10.1126/science.2536956. [DOI] [PubMed] [Google Scholar]
  37. Mustoe T. A., Cutler N. R., Allman R. M., Goode P. S., Deuel T. F., Prause J. A., Bear M., Serdar C. M., Pierce G. F. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Arch Surg. 1994 Feb;129(2):213–219. doi: 10.1001/archsurg.1994.01420260109015. [DOI] [PubMed] [Google Scholar]
  38. Mustoe T. A., Pierce G. F., Morishima C., Deuel T. F. Growth factor-induced acceleration of tissue repair through direct and inductive activities in a rabbit dermal ulcer model. J Clin Invest. 1991 Feb;87(2):694–703. doi: 10.1172/JCI115048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mustoe T. A., Tae Ahn S., Tarpley J. E., Pierce G. F. Role of hypoxia in growth factor responses: differential effects of basic fibroblast growth factor and platelet-derived growth factor in an ischemic wound model. Wound Repair Regen. 1994 Oct;2(4):277–283. doi: 10.1046/j.1524-475X.1994.20408.x. [DOI] [PubMed] [Google Scholar]
  40. Okamoto S., Inden M., Setsuda M., Konishi T., Nakano T. Effects of trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, in preventing restenosis after percutaneous transluminal coronary angioplasty. Am Heart J. 1992 Jun;123(6):1439–1444. doi: 10.1016/0002-8703(92)90792-t. [DOI] [PubMed] [Google Scholar]
  41. Paulsson Y., Hammacher A., Heldin C. H., Westermark B. Possible positive autocrine feedback in the prereplicative phase of human fibroblasts. Nature. 1987 Aug 20;328(6132):715–717. doi: 10.1038/328715a0. [DOI] [PubMed] [Google Scholar]
  42. Pepper M. S., Ferrara N., Orci L., Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992 Dec 15;189(2):824–831. doi: 10.1016/0006-291x(92)92277-5. [DOI] [PubMed] [Google Scholar]
  43. Peters K. G., De Vries C., Williams L. T. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8915–8919. doi: 10.1073/pnas.90.19.8915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Phillips G. D., Whitehead R. A., Knighton D. R. Initiation and pattern of angiogenesis in wound healing in the rat. Am J Anat. 1991 Nov;192(3):257–262. doi: 10.1002/aja.1001920305. [DOI] [PubMed] [Google Scholar]
  45. Pierce G. F., Mustoe T. A., Senior R. M., Reed J., Griffin G. L., Thomason A., Deuel T. F. In vivo incisional wound healing augmented by platelet-derived growth factor and recombinant c-sis gene homodimeric proteins. J Exp Med. 1988 Mar 1;167(3):974–987. doi: 10.1084/jem.167.3.974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Pierce G. F., Tarpley J. E., Allman R. M., Goode P. S., Serdar C. M., Morris B., Mustoe T. A., Vande Berg J. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB. Am J Pathol. 1994 Dec;145(6):1399–1410. [PMC free article] [PubMed] [Google Scholar]
  47. Pierce G. F., Tarpley J. E., Yanagihara D., Mustoe T. A., Fox G. M., Thomason A. Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. Am J Pathol. 1992 Jun;140(6):1375–1388. [PMC free article] [PubMed] [Google Scholar]
  48. Plate K. H., Breier G., Farrell C. L., Risau W. Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest. 1992 Oct;67(4):529–534. [PubMed] [Google Scholar]
  49. Plate K. H., Breier G., Millauer B., Ullrich A., Risau W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res. 1993 Dec 1;53(23):5822–5827. [PubMed] [Google Scholar]
  50. Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  51. Pu L. Q., Sniderman A. D., Brassard R., Lachapelle K. J., Graham A. M., Lisbona R., Symes J. F. Enhanced revascularization of the ischemic limb by angiogenic therapy. Circulation. 1993 Jul;88(1):208–215. doi: 10.1161/01.cir.88.1.208. [DOI] [PubMed] [Google Scholar]
  52. Rees M. J., Taylor G. I. A simplified lead oxide cadaver injection technique. Plast Reconstr Surg. 1986 Jan;77(1):141–145. doi: 10.1097/00006534-198601000-00023. [DOI] [PubMed] [Google Scholar]
  53. Risau W., Drexler H., Mironov V., Smits A., Siegbahn A., Funa K., Heldin C. H. Platelet-derived growth factor is angiogenic in vivo. Growth Factors. 1992;7(4):261–266. doi: 10.3109/08977199209046408. [DOI] [PubMed] [Google Scholar]
  54. Ross R., Glomset J., Kariya B., Harker L. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1207–1210. doi: 10.1073/pnas.71.4.1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Sato N., Beitz J. G., Kato J., Yamamoto M., Clark J. W., Calabresi P., Raymond A., Frackelton A. R., Jr Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am J Pathol. 1993 Apr;142(4):1119–1130. [PMC free article] [PubMed] [Google Scholar]
  56. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  57. Starksen N. F., Harsh G. R., 4th, Gibbs V. C., Williams L. T. Regulated expression of the platelet-derived growth factor A chain gene in microvascular endothelial cells. J Biol Chem. 1987 Oct 25;262(30):14381–14384. [PubMed] [Google Scholar]
  58. Sumi Y., Ueda M., Kaneda T., Oka T., Torii S. Marginal vascular change in pedicle skin flaps. Ann Plast Surg. 1986 Jan;16(1):68–74. doi: 10.1097/00000637-198601000-00007. [DOI] [PubMed] [Google Scholar]
  59. Sundberg C., Ljungström M., Lindmark G., Gerdin B., Rubin K. Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. Am J Pathol. 1993 Nov;143(5):1377–1388. [PMC free article] [PubMed] [Google Scholar]
  60. Takeshita S., Zheng L. P., Brogi E., Kearney M., Pu L. Q., Bunting S., Ferrara N., Symes J. F., Isner J. M. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest. 1994 Feb;93(2):662–670. doi: 10.1172/JCI117018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Unger E. F., Banai S., Shou M., Lazarous D. F., Jaklitsch M. T., Scheinowitz M., Correa R., Klingbeil C., Epstein S. E. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol. 1994 Apr;266(4 Pt 2):H1588–H1595. doi: 10.1152/ajpheart.1994.266.4.H1588. [DOI] [PubMed] [Google Scholar]
  62. Yanagisawa-Miwa A., Uchida Y., Nakamura F., Tomaru T., Kido H., Kamijo T., Sugimoto T., Kaji K., Utsuyama M., Kurashima C. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science. 1992 Sep 4;257(5075):1401–1403. doi: 10.1126/science.1382313. [DOI] [PubMed] [Google Scholar]

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