Thymosin-?4-mediated therapeutic neovascularization: role of the PI3K/AKT pathway.

Thymosin ?4 (T?4) is known to have pro-angogenic abilities in vitro and in vivo, and its cardioprotective effect is PI3/AKT-dependent. T?4-induced vessel formation requires transcriptional activation via the MRTF/SRF pathway. However, the relevance of PI3/AKT signaling for T?4-induced angiogenesis remains unclear. Here, we analyzed the PI3K/AKT cascade after T?4 transduction in models of chronic hindlimb ischemia.Tube formation assays of endothelial cells transfected with T?4 ± AKT-dn or PI3K?/Rho inhibition were performed. In mice, rAAV.T?4 was injected (intramuscular [i.m.]) 14 days before femoral artery ligation. In addition, either rAAV.AKT-dn was co-applied or Rho/PI3K/AKT pathways were inhibited. Capillary density and hindlimb perfusion were obtained. In rabbits, chronic ischemia was induced by femoral artery excision and subsequent i.m. injection of rAAV.T?4 ± rAAV.AKT-dn. Analyses of capillary density, collateral formation and perfusion were performed.T?4-induced ring formation was blunted by inhibiting the Rho-kinase (ROCK) or the PI3K/AKT pathway. In vivo, T?4 transduction induced angiogenesis and perfusion, an effect abrogated by inhibition of Rho-signaling, or PI3K?/AKT. In the rabbit model, inhibition of AKT in the lower limb not only abolished angiogenesis but also collateral formation.T?4 requires PI3K?/AKT pathway signaling for induction of therapeutic neovascularization in ischemic limb disease.     «

Thymosin ?4 (T?4) is known to have pro-angogenic abilities in vitro and in vivo, and its cardioprotective effect is PI3/AKT-dependent. T?4-induced vessel formation requires transcriptional activation via the MRTF/SRF pathway. However, the relevance of PI3/AKT signaling for T?4-induced angiogenesis remains unclear. Here, we analyzed the PI3K/AKT cascade after T?4 transduction in models of chronic hindlimb ischemia.Tube formation assays of endothelial cells transfected with T?4 ± AKT-dn or PI3K?/R...     »