Ligand oligomerization state controls Tie2 receptor trafficking and angiopoietin-2-specific responses.
Angiopoietins play important roles in the formation of neovessels and complex vascular networks. Angiopoietin (Ang)-1 and Ang-2 belong to a family of growth factors that display opposing effects on the activation of Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2). Endothelial Ang-2 expression is associated with vessel destabilization and regulates a balance between vascular regression and growth. To elucidate, in particular, the role of Ang-2 after arterial artery occlusion in the mouse limb, we applied a transgenic animal model with targeted Ang-2 expression in endothelial cells. We show here that restoration of blood flow in Ang-2:Tie1 transgenic mice is dramatically impaired when Ang-2 expression is induced in the vasculature. The defective restoration of perfusion in Ang-2 transgenic mice is evidenced by reduced collateral artery growth, which typically occurs to compensate for flow deficits after occlusion of the large conductance artery. Furthermore, reduced movement capacities and higher incidents of necrosis are consequently observed in the transgenic limbs as compared with controls. Mechanistically, the observed effects are attributed to defective smooth muscle cell recruitment in Ang-2 transgenic mice. Moreover, distinct Ang-2 levels in the genetically modified animals clearly correlated with the magnitude of reduced perfusion. In conclusion, our studies define Ang-2 as an important molecule for the progression of collateral artery growth and angiogenesis during ischemia and suggest precise Ang-2 dosage activities to accomplish blood vessel growth.