Dissecting TNFR2 signaling in arteriogenesis and angiogenesis

We have previously shown that TNF via TNFR2 elicits unique Etk‐dependent angiogenic signaling pathways in vascular endothelial cells (EC). Here we use TNFR2‐KO mice to define the roles of TNFR2 in vivo in several arteriogenesis/angiogenesis models Including ischemic hindlimb, inflammatory sponge, cornea and ear angiogenesis models. In a femoral artery ligation model TNFR2‐KO had reduced capacity in clinical recovery, limb perfusion and ischemic reserve capacity compared to the wild‐type mice. Consistently, ischemia‐initiated collateral growth (arteriogenesis) in the upper limb, and capillary formation and vessel maturation (angiogenesis) in the lower limb were reduced in TNFR2‐KO mice. Furthermore, our results suggest that vascular proliferation, but not infiltration of macrophage and lymphocytes, accounted for the defects of angiogenesis in TNFR2‐KO mice. Similar defects of angiogenesis in TNFR2‐KO mice were observed in other models. TNFR2 protein in vascular endothelium was highly upregulated in response to ischemia/inflammation, leading to increased TNFR2‐specific signaling as determined by the formation TNFR2‐TRAF2 complex and activation of TNFR2‐specific kinase Bmx/Etk. In isolated murine ECs, activation of TNFR2 induced NF‐κB‐dependent reporter gene expression, EC survival and migration. Further downstream effectors mediating TNFR2‐dependent arteriogenesis/angiogenesis will be discussed.