Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Nov 1, 1992; 176(5): 1375–1379.
PMCID: PMC2119412

Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing

Abstract

Persistent microvascular hyperpermeability to plasma proteins even after the cessation of injury is a characteristic but poorly understood feature of normal wound healing. It results in extravasation of fibrinogen that clots to form fibrin, which serves as a provisional matrix and promotes angiogenesis and scar formation. We present evidence indicating that vascular permeability factor (VPF; also known as vascular endothelial growth factor) may be responsible for the hyperpermeable state, as well as the angiogenesis, that are characteristic of healing wounds. Hyperpermeable blood vessels were identified in healing split-thickness guinea pig and rat punch biopsy skin wounds by their capacity to extravasate circulating macromolecular tracers (colloidal carbon, fluoresceinated dextran). Vascular permeability was maximal at 2-3 d, but persisted as late as 7 d after wounding. Leaky vessels were found initially at the wound edges and later in the subepidermal granulation tissue as keratinocytes migrated to cover the denuded wound surface. Angiogenesis was also prominent within this 7-d interval. In situ hybridization revealed that greatly increased amounts of VPF mRNA were expressed by keratinocytes, initially those at the wound edge, and, at later intervals, keratinocytes that migrated to cover the wound surface; occasional mononuclear cells also expressed VPF mRNA. Secreted VPF was detected by immunofluoroassay of medium from cultured human keratinocytes. These data identify keratinocytes as an important source of VPF gene transcript and protein, correlate VPF expression with persistent vascular hyperpermeability and angiogenesis, and suggest that VPF is an important cytokine in wound healing.

Full Text

The Full Text of this article is available as a PDF (660K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986 Dec 25;315(26):1650–1659. [PubMed]
  • Nathan C, Sporn M. Cytokines in context. J Cell Biol. 1991 Jun;113(5):981–986. [PMC free article] [PubMed]
  • Brown LF, Van de Water L, Harvey VS, Dvorak HF. Fibrinogen influx and accumulation of cross-linked fibrin in healing wounds and in tumor stroma. Am J Pathol. 1988 Mar;130(3):455–465. [PMC free article] [PubMed]
  • Breuing K, Eriksson E, Liu P, Miller DR. Healing of partial thickness porcine skin wounds in a liquid environment. J Surg Res. 1992 Jan;52(1):50–58. [PubMed]
  • Senger DR, Connolly DT, Van de Water L, Feder J, Dvorak HF. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 1990 Mar 15;50(6):1774–1778. [PubMed]
  • Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. [PubMed]
  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. [PubMed]
  • Gospodarowicz D, Abraham JA, Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7311–7315. [PMC free article] [PubMed]
  • Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan YC, Olander JV, Connolly DT, Stern D. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990 Dec 1;172(6):1535–1545. [PMC free article] [PubMed]
  • Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. [PMC free article] [PubMed]
  • Ffrench-Constant C, Van de Water L, Dvorak HF, Hynes RO. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol. 1989 Aug;109(2):903–914. [PMC free article] [PubMed]
  • Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol. 1988 Oct;133(1):95–109. [PMC free article] [PubMed]
  • Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed]
  • Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. [PubMed]
  • Dvorak HF, Harvey VS, Estrella P, Brown LF, McDonagh J, Dvorak AM. Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest. 1987 Dec;57(6):673–686. [PubMed]
  • Barker JN, Mitra RS, Griffiths CE, Dixit VM, Nickoloff BJ. Keratinocytes as initiators of inflammation. Lancet. 1991 Jan 26;337(8735):211–214. [PubMed]
  • Kupper TS. The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J Invest Dermatol. 1990 Jun;94(6 Suppl):146S–150S. [PubMed]
  • Nozaki S, Feliciani C, Sauder DN. Keratinocyte cytokines. Adv Dermatol. 1992;7:83–101. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...