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International Journal of Experimental Pathology logoLink to International Journal of Experimental Pathology
. 1994 Aug;75(4):243–255.

Angiogenesis and reinnervation in skin flaps: the effects of ischaemia examined in an animal model.

S Manek 1, G Terenghi 1, C Shurey 1, H Nishikawa 1, C J Green 1, J M Polak 1
PMCID: PMC2002245  PMID: 7524611

Abstract

In clinical flap transplantation, ischaemia may alter reinnervation patterns either directly or by affecting angiogenesis. This study presents the effects of ischaemia on innervation in totally denervated, transiently (30 minutes) or prolongedly ischaemic skin flaps studied immunohistochemically with antisera to PGP 9.5, CGRP and VWF. Following transient ischaemia, an increase in PGP-immunoreactive (PGP-IR) and CGRP-IR nerve fibres in distant skin by day 12 was followed by increased innervation in immediately adjacent skin. The latter increase was maintained up to 24 days which allowed near normal innervation at the suture margin and in adjacent flap tissue, 0.5 cm from the margin. There was concomitant reinnervation from the pedicle by day 24. In prolongedly ischaemic flaps, an earlier and more prolonged increase in innervation was seen in the entire surrounding skin, with innervation around the suture line at 24 days resembling that in the transiently ischaemic flaps despite initial complete nerve fibre depletion in this area. Hypertrophic nerve fibre clusters were seen in fibrotic areas overlying the pedicle. Vascular changes were similar in both groups with vascularization preceding reinnervation. There were no significant differences in reinnervation between the transiently and prolongedly ischaemic flaps at 24 days, despite considerable initial variations. Ischaemia, CGRP, mediators of chronic inflammation and epidermal factors appeared to stimulate angiogenesis and reinnervation.

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Selected References

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

  1. Aldskogius H., Hermanson A., Jonsson C. E. Reinnervation of experimental superficial wounds in rats. Plast Reconstr Surg. 1987 Apr;79(4):595–599. doi: 10.1097/00006534-198704000-00014. [DOI] [PubMed] [Google Scholar]
  2. Arnold F., West D. C. Angiogenesis in wound healing. Pharmacol Ther. 1991 Dec;52(3):407–422. doi: 10.1016/0163-7258(91)90034-j. [DOI] [PubMed] [Google Scholar]
  3. Brain S. D., Williams T. J., Tippins J. R., Morris H. R., MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator. Nature. 1985 Jan 3;313(5997):54–56. doi: 10.1038/313054a0. [DOI] [PubMed] [Google Scholar]
  4. Brown L. F., Yeo K. T., Berse B., Yeo T. K., Senger D. R., Dvorak H. F., van de Water L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992 Nov 1;176(5):1375–1379. doi: 10.1084/jem.176.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown M. C., Perry V. H., Lunn E. R., Gordon S., Heumann R. Macrophage dependence of peripheral sensory nerve regeneration: possible involvement of nerve growth factor. Neuron. 1991 Mar;6(3):359–370. doi: 10.1016/0896-6273(91)90245-u. [DOI] [PubMed] [Google Scholar]
  6. Denis-Donini S. Expression of dopaminergic phenotypes in the mouse olfactory bulb induced by the calcitonin gene-related peptide. Nature. 1989 Jun 29;339(6227):701–703. doi: 10.1038/339701a0. [DOI] [PubMed] [Google Scholar]
  7. Gloster A., Diamond J. Sympathetic nerves in adult rats regenerate normally and restore pilomotor function during an anti-NGF treatment that prevents their collateral sprouting. J Comp Neurol. 1992 Dec 15;326(3):363–374. doi: 10.1002/cne.903260305. [DOI] [PubMed] [Google Scholar]
  8. Gurney M. E., Yamamoto H., Kwon Y. Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor. J Neurosci. 1992 Aug;12(8):3241–3247. doi: 10.1523/JNEUROSCI.12-08-03241.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Haegerstrand A., Dalsgaard C. J., Jonzon B., Larsson O., Nilsson J. Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc Natl Acad Sci U S A. 1990 May;87(9):3299–3303. doi: 10.1073/pnas.87.9.3299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hall S. M. Regeneration in the peripheral nervous system. Neuropathol Appl Neurobiol. 1989 Nov-Dec;15(6):513–529. doi: 10.1111/j.1365-2990.1989.tb01251.x. [DOI] [PubMed] [Google Scholar]
  11. Hom D. B., Assefa G. Effects of endothelial cell growth factor on vascular compromised skin flaps. Arch Otolaryngol Head Neck Surg. 1992 Jun;118(6):624–628. doi: 10.1001/archotol.1992.01880060074016. [DOI] [PubMed] [Google Scholar]
  12. Jernbeck J., Edner M., Dalsgaard C. J., Pernow B. The effect of calcitonin gene-related peptide (CGRP) on human forearm blood flow. Clin Physiol. 1990 Jul;10(4):335–343. doi: 10.1111/j.1475-097x.1990.tb00795.x. [DOI] [PubMed] [Google Scholar]
  13. Karanth S. S., Dhital S., Springall D. R., Polak J. M. Reinnervation and neuropeptides in mouse skin flaps. J Auton Nerv Syst. 1990 Nov;31(2):127–134. doi: 10.1016/0165-1838(90)90069-u. [DOI] [PubMed] [Google Scholar]
  14. Khouri R. K., Brown D. M., Leal-Khouri S. M., Tark K. C., Shaw W. W. The effect of basic fibroblast growth factor on the neovascularisation process: skin flap survival and staged flap transfers. Br J Plast Surg. 1991 Nov-Dec;44(8):585–588. doi: 10.1016/0007-1226(91)90094-z. [DOI] [PubMed] [Google Scholar]
  15. Kjartansson J., Lundeberg T., Samuelson U. E., Dalsgaard C. J., Hedén P. Calcitonin gene-related peptide (CGRP) and transcutaneous electrical nerve stimulation (TENS) increase cutaneous blood flow in a musculocutaneous flap in the rat. Acta Physiol Scand. 1988 Sep;134(1):89–94. doi: 10.1111/j.1748-1716.1988.tb08463.x. [DOI] [PubMed] [Google Scholar]
  16. Knight K. R., Kawabata H., Coe S. A., Martin T. J., Angus J. A., O'Brien B. M. The salvage of rabbit ischaemic epigastric free flaps using the vasodilator calcitonin gene-related peptide. Br J Plast Surg. 1990 Jul;43(4):447–451. doi: 10.1016/0007-1226(90)90011-n. [DOI] [PubMed] [Google Scholar]
  17. Knighton D. R., Fiegel V. D. Regulation of cutaneous wound healing by growth factors and the microenvironment. Invest Radiol. 1991 Jun;26(6):604–611. doi: 10.1097/00004424-199106000-00020. [DOI] [PubMed] [Google Scholar]
  18. Kostakoğlu N., Manek S., Terenghi G., Polak J. M., Green C. J. Free sensate secondary skin flaps: an experimental study on patterns of reinnervation and neovascularisation. Br J Plast Surg. 1994 Jan;47(1):1–9. doi: 10.1016/0007-1226(94)90109-0. [DOI] [PubMed] [Google Scholar]
  19. Kreidstein M. L., Pang C. Y., Carlsen L. N., Xu N. Evidence for endothelium-dependent and endothelium-independent vasodilation in human skin flaps. Can J Physiol Pharmacol. 1992 Sep;70(9):1208–1216. doi: 10.1139/y92-168. [DOI] [PubMed] [Google Scholar]
  20. Lindholm D., Heumann R., Meyer M., Thoenen H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987 Dec 17;330(6149):658–659. doi: 10.1038/330658a0. [DOI] [PubMed] [Google Scholar]
  21. Manek S., Terenghi G., Shurey C., Nishikawa H., Green C. J., Polak J. M. Neovascularisation precedes neural changes in the rat groin skin flap following denervation: an immunohistochemical study. Br J Plast Surg. 1993 Jan;46(1):48–55. doi: 10.1016/0007-1226(93)90065-j. [DOI] [PubMed] [Google Scholar]
  22. May J. W., Jr, Chait L. A., O'Brien B. M., Hurley J. V. The no-reflow phenomenon in experimental free flaps. Plast Reconstr Surg. 1978 Feb;61(2):256–267. doi: 10.1097/00006534-197802000-00017. [DOI] [PubMed] [Google Scholar]
  23. Millican P. G., Poole M. D. Peripheral neovascularisation of muscle and musculocutaneous flaps. Br J Plast Surg. 1985 Jul;38(3):369–374. doi: 10.1016/0007-1226(85)90244-9. [DOI] [PubMed] [Google Scholar]
  24. Nishikawa H., Manek S., Fryer P. R., Green C. J. Reperfusion injury in rat adipomusculocutaneous flaps: an ultrastructural and microangiographic study. Br J Plast Surg. 1991 Oct;44(7):500–505. doi: 10.1016/0007-1226(91)90005-5. [DOI] [PubMed] [Google Scholar]
  25. Nishikawa H., Manek S., Green C. J. The oblique rat groin flap. Br J Plast Surg. 1991 May-Jun;44(4):295–298. doi: 10.1016/0007-1226(91)90075-u. [DOI] [PubMed] [Google Scholar]
  26. Schweigerer L., Neufeld G., Friedman J., Abraham J. A., Fiddes J. C., Gospodarowicz D. Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth. Nature. 1987 Jan 15;325(6101):257–259. doi: 10.1038/325257a0. [DOI] [PubMed] [Google Scholar]
  27. Serafin D., Shearin J. C., Georgiade N. G. The vascularization of free flaps: a clinical and experimental correlation. Plast Reconstr Surg. 1977 Aug;60(2):233–241. doi: 10.1097/00006534-197708000-00010. [DOI] [PubMed] [Google Scholar]
  28. Stark G. B., Hong C., Futrell J. W. Enhanced neovascularization of rat tubed pedicle flaps with low perfusion of the wound margin. Plast Reconstr Surg. 1987 Dec;80(6):814–824. doi: 10.1097/00006534-198712000-00010. [DOI] [PubMed] [Google Scholar]
  29. Sunderkötter C., Goebeler M., Schulze-Osthoff K., Bhardwaj R., Sorg C. Macrophage-derived angiogenesis factors. Pharmacol Ther. 1991;51(2):195–216. doi: 10.1016/0163-7258(91)90077-y. [DOI] [PubMed] [Google Scholar]
  30. Tron V. A., Coughlin M. D., Jang D. E., Stanisz J., Sauder D. N. Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). J Clin Invest. 1990 Apr;85(4):1085–1089. doi: 10.1172/JCI114539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tsur H., Daniller A., Strauch B. Neovascularization of skin flaps: route and timing. Plast Reconstr Surg. 1980 Jul;66(1):85–90. doi: 10.1097/00006534-198007000-00017. [DOI] [PubMed] [Google Scholar]
  32. Waris T. Innervation of scar tissue in the skin of the rat. Scand J Plast Reconstr Surg. 1978;12(3):173–180. doi: 10.3109/02844317809012992. [DOI] [PubMed] [Google Scholar]
  33. Westin M., Hedén P. Calcitonin gene-related peptide delays the no-reflow phenomenon in the rat island flap. Ann Plast Surg. 1988 Oct;21(4):329–334. doi: 10.1097/00000637-198810000-00006. [DOI] [PubMed] [Google Scholar]
  34. Yaar M., Grossman K., Eller M., Gilchrest B. A. Evidence for nerve growth factor-mediated paracrine effects in human epidermis. J Cell Biol. 1991 Nov;115(3):821–828. doi: 10.1083/jcb.115.3.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zdeblick T. A., Shaffer J. W., Field G. A. An ischemia-induced model of revascularization failure of replanted limbs. J Hand Surg Am. 1985 Jan;10(1):125–131. doi: 10.1016/s0363-5023(85)80263-x. [DOI] [PubMed] [Google Scholar]

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