Dynamic Regulation of Integrin α6β4 During Angiogenesis: Potential Implications for Pathogenic Wound Healing

OBJECTIVEAngiogenesis is an essential component of normal cutaneous wound repair, but is altered in pathogenic forms of wound healing, such as chronic wounds and fibrosis. We previously reported that endothelial expression of integrin α6β4 is developmentally regulated, with α6β4 expression correlating with tissue maturation and further showed that endothelial α6β4 is downregulated in explant angiogenesis assays. These data support the hypothesis that dynamic regulation of α6β4 may play an important role during new vessel formation in healing wounds. APPROACHTo test this hypothesis, we examined the endothelial expression of α6β4 using a murine model of cutaneous wound healing and in vitro cultures of primary human dermal microvascular endothelial cells (HDMECs). RESULTSExpression of α6β4 is downregulated during early stages of wound healing; angiogenic vessels in day 7 wounds do not express α6β4. Endothelial expression of α6β4 is resumed in day 14 wounds. Moreover, explanted HDMECs do not express α6β4, but expression is induced by treatment with histone deacetylase inhibitors. INNOVATIONWe provide in vivo data supporting a role for the dynamic regulation of α6β4 during vessel formation and remodeling during cutaneous wound repair and in vitro findings that suggest endothelial β4 expression is regulated transcriptionally, providing an important foundation for future studies to understand the transcriptional mechanisms involved in endothelial cell maturation during normal wound repair. CONCLUSIONOur data indicate that α6β4 is dynamically regulated during angiogenesis and vessel maturation and suggest that disruption of this regulation may contribute to defective angiogenesis associated with diabetic wounds or cutaneous fibrosis.