IRF3 and IRF7 mediate neovascularization via inflammatory cytokines

OBJECTIVE: To elucidate the role of interferon regulatory factor (IRF)3 and IRF7 in neovascularization. METHODS: Unilateral hind limb ischaemia was induced in Irf3(−/−), Irf7(−/−) and C57BL/6 mice by ligation of the left common femoral artery. Post‐ischaemic blood flow recovery in the paw was measured with laser Doppler perfusion imaging. Soleus, adductor and gastrocnemius muscles were harvested to investigate angiogenesis and arteriogenesis and inflammation. RESULTS: Post‐ischaemic blood flow recovery was decreased in Irf3(−/−)and Irf7(−/−) mice compared to C57BL/6 mice at all time points up to and including sacrifice, 28 days after surgery (t28). This was supported by a decrease in angiogenesis and arteriogenesis in soleus and adductor muscles of Irf3(−/−) and Irf7(−/−) mice at t28. Furthermore, the number of macrophages around arterioles in adductor muscles was decreased in Irf3(−/−)and Irf7(−/−) mice at t28. In addition, mRNA expression levels of pro‐inflammatory cytokines (tnfα, il6, ccl2) and growth factor receptor (vegfr2), were decreased in gastrocnemius muscles of Irf3(−/−) and Irf7(−/−) mice compared to C57BL/6 mice. CONCLUSION: Deficiency of IRF3 and IRF7 results in impaired post‐ischaemic blood flow recovery caused by attenuated angiogenesis and arteriogenesis linked to a lack of inflammatory components in ischaemic tissue. Therefore, IRF3 and IRF7 are essential regulators of neovascularization.