Suppression of integrin ?3?1 by ?9?1 in the epidermis controls the paracrine resolution of wound angiogenesis.

ABSTRACT: Development of wound therapies is hindered by poor understanding of combinatorial integrin function in the epidermis. In this study, we generated mice with epidermis-specific deletion of ?3?1, ?9?1, or both integrins as well as keratinocyte lines expressing these integrin combinations. Consistent with proangiogenic roles for ?3?1, ?3-null keratinocytes showed reduced paracrine stimulation of endothelial cell migration and survival, and wounds of epidermis-specific ?3 knockout mice displayed impaired angiogenesis. Interestingly, ?9?1 in keratinocytes suppressed ?3?1-mediated stimulation of endothelial cells, and wounds of epidermis-specific ?9 knockout mice displayed delayed vascular normalization and reduced endothelial apoptosis, indicating that ?9?1 cross-suppresses ?3?1 proangiogenic functions. Moreover, ?9?1 inhibited ?3?1 signaling downstream of focal adhesion kinase (FAK) autoactivation at the point of Src-mediated phosphorylation of FAK Y861/Y925. Finally, ?9?1 cross-suppressed many ?3?1-dependent genes, including the gene that encodes MMP-9, which we implicated as a regulator of integrin-dependent cross talk to endothelial cells. Our findings identify a novel physiological context for combinatorial integrin signaling, laying the foundation for therapeutic strategies that manipulate ?9?1 and/or ?3?1 during wound healing.

SUBMITTER: Longmate WM 

PROVIDER: S-EPMC5412555 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature