Histological evaluation of the effects of angiotensin peptides on wound repair in diabetic mice

Abstract

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.

Activation of skin renin–angiotensin system in diabetic rats

“…This proliferative effect is counteracted by the AT2 receptor, which can further initiate cell differentiation and apoptosis. Stimulating AT1 receptor could also cause increased collagen synthesis and reduced degradation, while the reverse could happen if stimulating AT2 receptor [4].…”

“…AngII affects proliferation, apoptosis, migration, collagen metabolism, and capillary formation of skin cells via its receptors [4]. The local expression of AngII is therefore likely to be important in pathological damage, wound healing, and scar formation of the skin [2,5].…”

Angiotensin II regulates phosphoinositide 3 kinase/Akt cascade via a negative crosstalk between AT1 and AT2 receptors in skin fibroblasts of human hypertrophic scars

“…In rodents, it has been documented that Life Sciences 79 (2006) 475 -483 www.elsevier.com/locate/lifescie there is an increased level of Ang II or Ang-converting enzyme (ACE) in the rat skin (Gyurko et al, 1992;Sun and Weber, 1996) during wound healing, an upregulation of AT 1 or AT 2 receptor in wounded skin (Abiko et al, 1996;Kimura et al, 1992;Viswanathan and Saavedra, 1992), and that the topical administration of Ang II accelerates skin wound healing (Rodgers et al, 1997(Rodgers et al, , 2001(Rodgers et al, , 2003. Interestingly, as previously mentioned, AT 1 and AT 2 receptors play opposite roles in regulation of cellular metabolism and proliferation in skin cells such as skin fibroblasts (Gyurko et al, 1992;Takeda et al, 2004;Min et al, 2004).…”

NorLeu3-Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers

“…In the preclinical optimization of the product, it was noted that the wound first filled in with the extracellular matrix that was similar to normal skin and then the wound was re-epithelialized presenting histologically as nearly scarless healing. 1,2 Similarly, clinical studies showed a reduction in the volume of the wound, followed by the reduction in area, and then closure confirming the translation of preclinical pharmacology studies into clinical benefit.…”