Fibromodulin Enhances Angiogenesis during Cutaneous Wound Healing

Abstract

Background: Fibromodulin (FMOD) plays a critical role in the wound-healing process. Our previous studies revealed that FMOD deficiency led to marked alterations in adult wound healing characterized by delayed dermal cell migration, postponed wound closure, and increased scar formation, all accompanied by impeded angiogenesis. Therefore, the aim of this study was to reveal the effect of FMOD on angiogenesis during the wound-healing process. Methods: In vivo angiogenic effects of FMOD were assessed by a chick embryo chorioallantoic membrane assay, a Matrigel (BD Bioscience, Franklin Lakes, N.J.) plug implant assay, and rodent primary closure wound models. In vitro angiogenic effects of FMOD were recorded by cell invasion and dimensional and topological parameters of human umbilical vein endothelial cells. Results: We provided evidence that FMOD significantly enhanced vascularization: first, FMOD boosted blood vessel formation on the chorioallantoic membrane; second, FMOD markedly stimulated capillary infiltration into Matrigel plugs subcutaneously implanted in adult mice; and finally, FMOD robustly promoted angiogenesis in multiple adult rodent cutaneous wound models. Furthermore, FMOD administration restored the vascularity of fmod−/− mouse wounds. In support of this, FMOD endorsed an angiogenesis-favored microenvironment in adult rodent wounds not only by upregulating angiogenic genes but also by downregulating angiostatic genes. In addition, FMOD significantly enhanced human umbilical vein endothelial cell invasion and tube-like structure formation in vitro. Conclusions: Altogether, we demonstrated that in addition to reducing scar formation, FMOD also promotes angiogenesis. As blood vessels organize and regulate wound healing, its potent angiogenic properties will further expand the clinical application of FMOD for cutaneous healing of poorly vascularized wounds.