Abstract
The angiopoietins (ANGPT) are ligands for the endothelial cell (EC) receptor tyrosine kinase, Tie2. Angpt-1 is a Tie2 agonist that promotes vascular maturation and stabilization, whereas Angpt-2 is a partial agonist/antagonist involved in the initiation of postnatal angiogenesis. Therefore, we hypothesized that overexpression of Angpt-2 would be more effective than Angpt-1 for enhancing the perfusion recovery in the ischemic hindlimb. Perfusion recovery was markedly impaired in Tie2-deficient animals at day 35 in a model of chronic hindlimb ischemia. Injections of Angpt-2 or VEGFA plasmid at 7 days post femoral artery resection enhanced recovery and improved arteriogenesis as assessed by angiographic scores, whereas Angpt-1 or null plasmid had no effect. In addition, Angpt-2 together with VEGF resulted in greater improvement in perfusion and collateral vessel formation than VEGF alone. Similarly, conditional overexpression of Angpt-2 in mice improved ischemic limb blood flow recovery, while Angpt-1 overexpression was ineffective. These data from Tie2 heterozygote deficient mice demonstrate, for the first time, the importance of the Tie2 pathway in spontaneous neovascularization in response to chronic hindlimb ischemia. Moreover, they show that overexpression of the partial agonist, Angpt-2, but not Angpt-1, enhanced ischemic hind limb perfusion recovery and collateralization, suggesting that a coordinated sequence antagonist and agonist activity is required for effective therapeutic revascularization.
Highlights
The endothelial-selective receptor tyrosine kinase (RTK), Tie2, plays an essential role in blood vessel formation during embryonic development [1]
Femoral ligation with limited excision resulted in a stable model of chronic hindlimb ischemia without evidence of limb necrosis and tissue loss in either Tie2-deficient or WT mice
Recovery of perfusion in the ischemic (I) vs. the nonoperated (NI) limb was reduced in Tie2 deficient compared to WT mice at day 35 (I/NI 0.4260.04 vs.0.7960.06, respectively; p,0.001) (Figure 2c)
Summary
The endothelial-selective receptor tyrosine kinase (RTK), Tie, plays an essential role in blood vessel formation during embryonic development [1]. It has recently been recognized that Angpt-2 exhibits contextdependent agonist activity, inducing activation of Tie-2 in a timedependent manner to levels similar to Angpt-1 at high concentrations [13] or during prolonged (i.e. 12 to 24 hours) exposure [14], which corresponds to the time course of capillary-like network formation in cultured ECs [14] These findings point to a possible role for Angpt-2, as an inhibitor of Tie in the initiation of the angiogenic response, and as an agonist in the later stages of blood vessel formation and maturation that are dependent on Tie-2 activation [7]
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