IRF3 and IRF7 mediate neovascularization via inflammatory cytokines

Abstract

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.

Keywords: angiogenesis; arteriogenesis; inflammation; interferon regulatory factor; neovascularization.