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Early Inducible Nitric Oxide Synthase 2 (NOS 2) Activity Enhances Ischaemic Skin Flap Survival

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Abstract

A functional skin-flap model of angiogenesis in the mouse was utilized to investigate ischaemic flap survival/angiogenesis whilst under pharmacological or genetic inhibition of nitric oxide synthase (NOS). In this model, the epigastric artery was cauterized. Following a five-day angiogenic period an abdominal skin-flap supplied by the pre-existing epigastric artery was raised and resutured. After a further six days the outcome was determined by measuring the area of living skin-flap that was sustained by new vessel growth around the cauterized artery. Both pharmacological [S-methyl-isothiourea (SMT) given via i.p. injection for the five-day angiogenic period] and genetic inhibition of NOS 2 (using NOS 2−/− mice) caused a similar and significant fall in flap survival compared to saline-treated wild-type mice (P < 0.05). Delaying pharmacological NOS 2 inhibition for two days post-arterial cauterization increased flap survival in wild-type mice to that of saline-treated controls, whilst treating wild-type mice with SMT for only the first three days of angiogenesis produced a significant decrease in flap survival, similar to that of five-day SMT-treated wild types. Immunoreactivity for NOS 2 in NOS 2−/− knockout mice was absent in both pedicles and skin-flaps, whilst mast cells from both the pedicle and the skin-flap stained positively for NOS 2 in wild-type mice. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF 2) immunoreactivity was also strongly evident in mast cells of both wild-type and NOS 2−/− mice at both sites. These results point to a significant role for NOS 2 in promoting wound healing/angiogenesis in its early stages.

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Authors and Affiliations

  1. Plastic and Reconstructive Surgery, Suwa Red Cross Hospital, Kogan-Douri, Suwa, Japan

    Sunao Furuta & Geraldine Mitchell

  2. Bernard O'Brien Institute of Microsurgery and Department of Surgery, University of Melbourne, St. Vincent's Hospital, Fitzroy, Melbourne, Victoria, Australia

    Peter Vadiveloo, Rosalind Romeo-Meeuw & Wayne Morrison

  3. Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia

    Alastair Stewart

Authors
  1. Sunao Furuta
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  2. Peter Vadiveloo
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  3. Rosalind Romeo-Meeuw
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  4. Wayne Morrison
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  5. Alastair Stewart
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  6. Geraldine Mitchell
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Furuta, S., Vadiveloo, P., Romeo-Meeuw, R. et al. Early Inducible Nitric Oxide Synthase 2 (NOS 2) Activity Enhances Ischaemic Skin Flap Survival. Angiogenesis 7, 33–43 (2004). https://doi.org/10.1023/B:AGEN.0000037328.86329.8b

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  • DOI: https://doi.org/10.1023/B:AGEN.0000037328.86329.8b

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