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Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, D-60590 Frankfurt am Main, Germany
2Correspondence: Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JWG-Universität Frankfurt/M., Theodor-Stern-Kai 7, D-60590 Frankfurt/M., Germany. E-mail: Pfeilschifter{at}em.uni-frankfurt.de
Recently, we demonstrated a large induction of inducible nitric oxide
synthase (iNOS) during cutaneous wound repair. In this study, we
investigated the role of nitric oxide (NO) for the expression of
vascular endothelial growth factor (VEGF), which represents the most
important angiogenic factor during the proliferative phase of skin
repair. Since keratinocytes are the major source of VEGF production
during this process, we used cultured keratinocytes (HaCaT cell line)
as an in vitro model to investigate NO action on growth
factor- and cytokine-stimulated VEGF expression. Exogenously added NO
enhanced transforming growth factor-ß1-, keratinocyte growth factor-,
interleukin-1ß-, tumor necrosis factor-
-, and
interferon-
-induced VEGF mRNA and protein synthesis in
keratinocytes. We could demonstrate that high-level expression of
cytokine-induced VEGF mRNA in keratinocytes is dependent on
endogenously produced NO, as inhibition of the coinduced iNOS by
NG-monomethyl-L-arginine (L-NMMA) markedly decreased
cytokine-triggered VEGF mRNA levels in the cells. We also established
an in vivo model in mice to investigate the role of NO
during wound healing. During excisional wound repair, mice were treated
with L-N6-(1-iminoethyl)lysine (L-NIL), a selective
inhibitor of iNOS enzymatic activity. Compared to control mice,
L-NIL-treated animals were characterized by markedly reduced VEGF mRNA
levels during the inflammatory phase of repair. Immunohistochemistry
demonstrated reduced VEGF protein expression and a completely
disorganized pattern of VEGF-expressing keratinocytes within the
hyperproliferative epithelium at the wound edge in L-NIL-treated mice.
We demonstrate that triggering of VEGF expression is a crucial
molecular mechanism underlying NO function during wound
healing.—Frank, S., Stallmeyer, B., Kämpfer, H., Kolb, N.,
Pfeilschifter, J. Nitric oxide triggers enhanced induction of vascular
endothelial growth factor expression in cultured keratinocytes (HaCaT)
and during cutaneous wound repair.
Key Words: gene expression regulation • skin • inducible nitric oxide synthase
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