Diabetes impairs multiple aspects of the wound-healing response. Delayed wound healing continues to be a significant healthcare problem for which effective therapies are lacking. We have hypothesized that local delivery of mesenchymal stromal cells (MSC) at a wound might correct many of the wound-healing impairments seen in diabetic lesions. We treated excisional wounds of genetically diabetic (Db-/Db-) mice and heterozygous controls with either MSC, CD45(+) cells, or vehicle. At 7 days, treatment with MSC resulted in a decrease in the epithelial gap from 3.2 +/- 0.5 mm in vehicle-treated wounds to 1.3 +/- 0.4 mm in MSC-treated wounds and an increase in granulation tissue from 0.8 +/- 0.3 mm(2) to 2.4 +/- 0.6 mm(2), respectively (mean +/- SD, P < 0.04). MSC-treated wounds also displayed a higher density of CD31(+) vessels and exhibited increases in the production of mRNA for epidermal growth factor, transforming growth factor beta 1, vascular endothelial growth factor, and stromal-derived growth factor 1-alpha. MSC also demonstrated greater contractile ability than fibroblast controls in a collagen gel contraction assay. The effects of locally applied MSC are thus sufficient to improve healing in diabetic mice. Possible mechanisms of this effect include augmented local growth-factor production, improved neovascularization, enhanced cellular recruitment to wounds, and improved wound contraction.

Restenosis is the major limitation of the long-term success of percutaneous transluminal coronary angioplasty. The process of restenosis involves repair of vascular injury and remodeling of vessel architecture. Therapeutic interventions that improve vascular function may therefore be beneficial in the treatment of restenosis. Antioxidants such as probucol and vitamins C and E have proved effective in improving endothelial function in hypercholesterolemia, inhibiting lipid accumulation in animal models of atherosclerosis, and decreasing cardiovascular mortality in humans. Forty-two female domestic swine were divided into four study groups: control (n = 12); vitamin C (500 mg/d, group C, n = 9); vitamin E (1000 U/d, group E, n = 10); and vitamins C and E (500 mg/d + 1000 U/d, group C+E, n = 11) before oversized balloon injury of the left anterior descending and circumflex coronary arteries. Vitamins were administered 7 days before balloon injury and continued until the swine were killed 14 days after injury. Significant differences in morphometric parameters were present only in group C+E, with increases in vessel and lumen area in the segment with maximal injury. Although there was no decrease in intima area or in maximal intima thickness, the ratio of intima area to vessel area was significantly reduced, consistent with a positive effect in group C+E. Graphic analysis of the relationship between initial vessel injury (using internal elastic lamina fracture length/lumen perimeter) and vessel response to injury (using intima area/vessel area) for all segments showed improved indices for group C+E (P < .005). The beneficial effect of vitamins correlated with changes in lipid redox state. Low-density lipoprotein (LDL) thiobarbituric acid-reactive substances showed an approximately 70% decrease in all treatment groups, and the lag phase for LDL-conjugated diene formation was significantly increased, with group C+E > group E > group C. The combination of vitamins C and E improved vascular response to injury because of an apparent beneficial effect on vascular remodeling. The fact that the combination of vitamins C+E was better than vitamin E or vitamin C alone is consistent with the ability of vitamin C to improve the antioxidant effect of vitamin E, suggesting that the improved vessel response was due to a change in redox state. This study suggests an important role for oxygen radicals in the vascular response to injury and suggests that vascular remodeling and intimal proliferation are important to the restenotic process.

Angiotensin-converting enzyme (ACE) activity plays a central role in vessel growth and remodeling as shown by the fact that ACE inhibitors reduce neointimal proliferation after rat carotid injury. To investigate the mechanisms that regulate smooth muscle cell ACE expression, we studied the effects of steroids on ACE activity and mRNA in cultured rat aortic smooth muscle cells. ACE activity was present at low levels independent of growth state. In response to the glucocorticoid dexamethasone (100 nmol/L for 72 hours), ACE activity (hydrolysis of [3H]benzoyl-Phe-Ala-Pro) increased 10.1 +/- 3.1-fold. The increase in activity occurred within 12 hours and peaked after 72 hours of treatment. The increase in ACE activity was specific for glucocorticoids and paralleled their potency (dexamethasone > hydrocortisone = prednisolone). Dexamethasone increased the steady-state level of ACE mRNA in a concentration-dependent manner (21.4 +/- 0.4-fold at 100 nmol/L for 72 hours). Dexamethasone stimulation of ACE expression appeared to be due to both increased transcription and stabilization of ACE enzyme mRNA. This was suggested by the finding that dexamethasone stimulated nuclear run-on expression of ACE mRNA by only threefold, in contrast to the 21-fold increase in steady-state mRNA. These findings establish that ACE is a dynamically regulated enzyme in rat aortic smooth muscle cells. In addition, the present findings suggest an important role for stress steroids in the vascular response to injury in vivo.