Abstract
Although the inflammatory and proliferative phases of wound healing have been well described, much less is known about how healing resolves. During the resolution phase, pruning of the capillary bed and maturation of capillaries occurs and influences the final strength and fidelity of the wound. PEDF, an endogenous anti-angiogenic factor, is produced in wounds and may contribute to the removal of capillaries during wound resolution. This study utilized PEDF−/− mice to examine how PEDF influences wound angiogenesis, particularly capillary density and permeability. The absence of PEDF led to transient changes in dermal wound closure and collagen content, but caused substantial changes in wound angiogenesis. Compared to wild type (WT) mice, wounds from PEDF−/− mice exhibited a significant increase in capillaries during the proangiogenic phase of repair, and a delay in capillary pruning. Conversely, the addition of rPEDF caused a reduction in capillary density within skin wounds in WT mice. In vitro studies showed that PEDF inhibited migration and tube formation by dermal microvascular endothelial cells, and caused a decrease in the expression of VEGFR2, VCAM-1, and other surface receptors. The results demonstrate that loss of PEDF causes a distinctive wound healing phenotype that is characterized by increased angiogenesis and delayed resolution. The findings suggest that PEDF most likely acts through multiple mechanisms to regulate proper capillary refinement in wounds.
Highlights
The regulation of wound resolution remains incompletely understood, the mechanisms that contribute to the ordered regression of capillaries
Since inflammation is known to influence wound healing, and because increased inflammation is often linked to the angiogenic response, we examined whether changes in inflammation might be involved in the observed changes in angiogenesis seen in PEDF−/− mice
No significant differences were seen in macrophage content. These results suggest that the increased angiogenesis seen in PEDF−/− mice does not derive from altered inflammation, but is most likely a direct result of the loss of PEDF anti-angiogenic activity on endothelial cells themselves
Summary
The regulation of wound resolution remains incompletely understood, the mechanisms that contribute to the ordered regression of capillaries. Prior studies in our lab have suggested that PEDF, a known endogenous anti-angiogenic protein, provides important signals that lead to capillary removal during this phase of repair[6]. The anti-angiogenic capability of PEDF has been best described in tissues other than skin, yet the mechanisms by which PEDF might influence capillary reduction in skin wounds are not yet well studied[7,8,9,10]. The results demonstrate that the absence of PEDF leads to specific changes in the proliferative phase of healing, and causes a distinctive delay in wound resolution. The data further shows that PEDF has many direct effects on dermal microvascular endothelial cell function, and suggest a multi-factorial role for PEDF in the remodeling phases of dermal wound healing
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