Dynamic Regulation of Integrin α 6 β 4 During Angiogenesis: Potential Implications for Pathogenic Wound Healing

Abstract

Objective:

Angiogenesis 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.

Approach:

To 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).

Results:

Expression 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.

Innovation:

We 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.

Conclusion:

Our 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.