Abstract 299: Impaired Inflammatory Angiogenesis in the Context of Aging is the Result of the Uncoupling of Macrophage Il-1beta-VEGF Expression and the Switch of VEGF Isoforms

Abstract

Aging and age-related diseases like peripheral artery disease (PAD) is associated with impairedinflammatory angiogenesis responses to injury. Critical ischemic limb and wound injury animalmodels, have shown impact of inflammatory monocytes/macrophages as a major source ofproangiogenic mediators leading to new arterial growth and healing. In hind limb ischemia mousemodel of PAD, we have recently demonstrated the loss of macrophage IL-1β expression leads todecreased VEGF-A (total) and VEGF-A165a expression (proangiogenic isoform), while VEGF-A165b (inhibitory isoform) was increased, under the regulation of transcription factors SignalTransducer and Activator of Transcription 3 (STAT3) and Nuclear Factor Kappa B (NF-κB).Previous studies on aged mice have shown impaired of blood flow recovery and reduced VEGF-A expression. Moreover, recombinant VEGF-A administration did not fully overcome the footperfusion and prevent limb salvage. The mechanisms of reduced VEGF-A expression in aged animals remains incomplete. Our data from advanced aged (104-week-old) mice demonstratereduced blood flow recovery after excision of the femoral artery and reduced VEGF-A and VEGF-A165a in ischemic muscle tissue compared to young (12-week-old) while IL-1β and VEGF-A165bwere increased. Bone marrow-derived-macrophages (BMDMs) from 104-week-old alsodemonstrate decreased VEGF-A and VEGF-A165a expression. IL-1β andVEGF-A165b were foundincreased. Lastly, polarized BMDMs from 12-week-old demonstrate increased VEGFR2expression in inflammatory “M1” macrophages while VEGFR1 was increased in alternativelyactivated “M2" macrophages. Interestingly, 104-week-old demonstrate significantly increasedVEGFR1 expression while VEGFR2 was reduced compared to 12-week-old. We hypothesize thatthe regulation of IL-1β-VEGF-A axis and the type of VEGFR1/R2 involved in the signalingcomplex determine the fate of angiogenesis responses to injury in the context of advanced age.Our goals will be to define mechanisms whereby aging is associated with uncoupling of IL-1β andVEGF-A expression then, how VEGF-A isoforms and VEGFR1/2 signaling complex axis regulateinflammatory angiogenesis.