Wound chronicity and limb loss are major complications of peripheral arterial occlusive disease. The poor wound healing properties are attributed to dysfunctional angiogenesis, as the re-establishment of a mature microvasculature is requisite. Neovascularization is accomplished by multiplication and migration of endothelial cells (EC), which digest the basement membrane and travel into the wound base by recruiting MMP-2 to their surface via integrin alpha-v-beta3. Following integrin binding, MMP-2 eventually becomes unstable and autocatalyzes, releasing its hemopexin domain (PEX2). After reaching sufficient quantities, PEX2 competes for integrin receptors and prevents MMP-2 localization. Chronically ischemic limbs undergo prolonged arteriogenesis in the effort to revascularize hypoxic territories via collateralization. As PEX2 is a byproduct of angiogenesis, hindlimb tissue levels are likely to be elevated. In vivo studies demonstrate a significant decline in angiogenesis in the presence of elevated PEX2 concentrations. Evidence suggests that prolonged arteriogenesis elevates tissue PEX2 concentrations and predisposes to poor wound healing by inhibition of MMP-2 EC localization, EC migration and tubule formation. The EC dysfunction results in failure to form a stable microvasculature with which to nourish the healing wound.
