We have previously demonstrated that keratinocyte-specific forkhead box O1 (FOXO1) deletion interferes with keratinocyte migration in normal skin wounds. However it has an opposite effect in diabetic skin wounds, significantly improving the healing response. In addition we found that skin epithelium regulates connective tissue healing mediated by FOXO1, which is strongly associated with wound angiogenesis in our microarray results. However, a role for keratinocytes in this complex process has yet to be investigated. To this end, we investigated possible involvement of gingival keratinocytes in connective tissue healing under both normal and diabetic conditions. We found that keratinocyte-specific FOXO1 deletion interfered with normal gingival connective tissue healing by decreasing granulation tissue formation and angiogenesis, which were mediated by vascular endothelial growth factor A (VEGF-A). In particular this is the first evidence that avascular epithelium regulates angiogenesis involving the VEGF-A secretion mediated by FOXO1. Furthermore, we investigated the possible role of epithelial to mesenchymal transition (EMT) during wound healing using the lineage tracing in transgenic mice. But we did not find any keratinocyte-specific reporter activity in the connective tissue indicating that there was no apparent trans-differentiation of keratinocytes into typical fibroblasts or myofibroblasts during wound healing. These results establish an important role of epithelial cells in accelerating wound angiogenesis and connective tissue healing through a FOXO1-dependent mechanism.