Recent studies have shown that angiotensin peptides accelerate dermal repair. Histological observation of samples taken at the termination of studies showed that the wounds treated with peptides were mature and organized by day 25 after full thickness excision in diabetic mice. However, the mechanisms by which this acceleration occurs has not been determined. In the experiments described here, the effect of angiotensin peptides (AII, A(1-7) and NorLeu (3)-A(1-7) on the quality of the healing wound was evaluated histologically. Administration of the peptides accelerated collagen deposition, re-epithelialization and new blood vessels formation. By day 4, the percentage of the wound with collagen increased two- to six-fold depending upon the peptide. The increase by angiotensin peptides continued throughout the experimental period. On days 4 and 7 9 (only) after injury, exposure to angiotensin peptides increased the number of blood vessels at wound site two-to three-fold. Finally, the percentage of the wound site covered with new epithelium increased after administration of angiotensin peptides. Re-epithelialization was observed as early as day 4 in wounds treated ith angiotensin peptides. The increase was greater at later time points (up to 8-fold ar day 14 with NorLeu(3)-A(1-7) had an increase in neutrophils and macrophages on day 4 after wounding. Overall, administration of these peptides resulted in a healing site that was more mature, including reorganization of the collagen into a basket-weave appearance. Further, these studies confirm the superiority of NorLeu(3)-A(1-7) to AII and A(1-7) in wound healing evaluated at a microscopic level.

Angiotensin II has been shown to be a potent agent in the acceleration of wound repair. Angiotensin (1-7), a fragment of angiotensin II that is not hypertensive, was found to be comparable to angiotensin II in accelerating dermal healing. This activity was evaluated in four models: rat and diabetic mouse full-thickness excisional wounds; rat random flap; and guinea pig partial thickness thermal injury. In all models, angiotensin (1-7) was comparable to angiotensin II. Angiotensin (1-7) accelerated the closure of wounds in diabetic mice and rats. In diabetic mice the resultant tissue at day 25 after injury was more comparable to normal tissue than the fibrotic scar observed in placebo-treated wounds. In the random flap model, angiotensin (1-7) was comparable to angiotensin II in maintaining flap viability (approximately 82%) and flap survival (40%). Finally, angiotensin (1-7) increased proliferation in the hair follicles at the edge of the wound and site of thermal injury, and the number of patent blood vessels on day 7 after partial thickness thermal injury. These data may be partially explained by the effect of angiotensin II and angiotensin (1-7) on keratinocyte proliferation. While platelet-derived growth factor had no effect on keratinocyte proliferation, angiotensin II and angiotensin (1-7) significantly increased keratinocyte proliferation. These data show that angiotensin(1-7) is comparable to angiotensin II in accelerating skin repair. Furthermore, the hypertensive and wound healing effects can be separated within the family of angiotensin peptides.

Angiotensin peptides have been demonstrated to modulate cellular proliferation, angiogenesis, and dermal repair. In this report, the effects of an analogue of the active angiotensin peptide angiotensin(1-7), namely norLeu3-angiotensin(1-7) (NorLeu3-A(1-7)), on the healing of epithelial wounds are presented. Three models were used to evaluate the normal (rats) and delayed (diabetic mice) healing responses of full-thickness excision wounds and the healing responses of full-thickness incision wounds (rats). NorLeu3-A(1-7) was superior to the naturally occurring angiotensin peptide angiotensin(1-7) and to Regranex (Ortho McNeil, Somerville, N.J.) (a formulation of recombinant platelet-derived growth factor used clinically for the treatment of diabetic ulcers) in accelerating tissue repair. By day 9 (normal rats) and day 11 (diabetic mice), the differences in the rates of closure of full-thickness excision wounds between NorLeu3-A(1-7) and Regranex were statistically significant (n = 5 per group). Full healing was observed for 60 percent of the diabetic mice treated topically with NorLeu3-A(1-7) by day 18 after injury, at which time full healing of wounds on placebo-treated or Regranex-treated diabetic mice was not observed. In the rat incision model, accelerated healing and reduced gross appearance of scarification were observed. Administration of NorLeu3-A(1-7) reduced fibrosis and scarring in the healing wounds. This action was more pronounced with longer administration of the peptide after injury. In fact, if systemic administration of the peptide (NorLeu3-A(1-7)) was continued during the remodeling phase, then the formation of new adnexal structures at the center of full-thickness excision wounds was observed, with an increase in the appearance of small immature hair follicles at the sites of the excision wounds. The action of this peptide was blocked by the AT receptor antagonist d-Ala7-angiotensin(1-7), which suggests that this receptor is involved in the healing responses to exogenous NorLeu3-A(1-7). These data suggest that this novel angiotensin peptide has the potential to be of benefit in accelerating wound repair and reducing scar formation.

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