Expressional regulation of angiopoietin-1 and-2 and the tie-1 and-2 receptor tyrosine kinases during cutaneous wound healing: A comparative study of normal and impaired repair

It has become evident that a closely regulated presence of vascular endothe lial growth factor (VEGF) and angiopoietin (Ang) factors determines the fat e of blood vessel formation during angiogenesis. As angiogenesis is central to a normal wound-healing process, we investigated the regulation of Ang-1 and -2 and the related tyrosine kinase with immunoglobulin and epidermal g rowth factor homology (Tie)-1 and -2 receptors during normal repair in Balb /c mice and diabetes-impaired wound healing conditions in genetically diabe tic (db/db) mice. For both normal and impaired healing conditions, we obser ved a constitutive expression of Ang-1, which was paralleled by an increase of Ang-2 upon injury. Whereas the observed Ang-2 expression declines from Day 7 after injury in control mice, diabetic-impaired healing was character ized by still increasing amounts of Ang-2 at these time points. Furthermore , Tie-1 was strongly induced during repair with a prolonged expression in d iabetic mice, whereas Tie-2 expression was constitutive during normal repai r but completely absent in diabetes-impaired healing. The overexpression of Ang-2 in the presence of markedly reduced VEGF in wounds of diabetic mice was associated with a dramatic decrease in endothelial cell numbers compare d with normal healing as assessed by analysis of the endothelium-specific m arkers CD31 and von Willebrand factor, whereas the lymphatic endothelium re mained stable as determined by expression of VEGF receptor-3 (VEGFR-3/Flt-4 ).