Angiopoietin-2 stimulates blood flow recovery after femoral artery occlusion by inducing inflammation and arteriogenesis

Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1989-95. doi: 10.1161/ATVBAHA.108.175463. Epub 2008 Sep 4.


Objective: Recently, we have shown that shear stress regulates the angiogenic potential of endothelial cells in vitro by an Angiopoietin-2 (Ang2)-dependent mechanism; however its pathophysiological significance in vivo was not clear. We hypothesized that Ang2 plays an important role in blood flow recovery after arterial occlusion in vivo by regulating angiogenesis and arteriogenesis.

Methods and results: C57Bl/6J mice underwent femoral artery ligation and were injected with a specific Ang2 inhibitor, L1-10, or vehicle for 10 days. Ang2 mRNA was upregulated at day 2, and Ang2 protein was upregulated at day 2, 5, and 7 in the ligated hindlimb. L1-10 treatment significantly blunted blood flow recovery. L1-10 decreased smooth muscle cell coverage of neovessels without affecting capillary density, suggesting a specific role for Ang2 in arteriogenesis. Mechanistically, L1-10 decreased expression of intercellular and vascular cell adhesion molecules as well as infiltrating monocytes/macrophages in the ischemic tissue. Although L1-10 had no effect on the number of CD11b+ cells (monocytes/macrophages) mobilized in the bone marrow, it maintained elevated numbers of circulating CD11b+ cells in the peripheral blood.

Conclusions: These results suggest that Ang2 induced in ischemic tissue plays a critical role in blood flow recovery by stimulating inflammation and arteriogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiopoietin-1 / metabolism
  • Angiopoietin-2 / antagonists & inhibitors
  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism*
  • Animals
  • Arterial Occlusive Diseases / complications*
  • Arterial Occlusive Diseases / metabolism
  • Arterial Occlusive Diseases / physiopathology
  • CD11b Antigen / blood
  • Cells, Cultured
  • Collateral Circulation
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Femoral Artery / surgery
  • Humans
  • Inflammation / metabolism*
  • Inflammation / physiopathology
  • Intercellular Adhesion Molecule-1 / metabolism
  • Ischemia / etiology
  • Ischemia / metabolism*
  • Ischemia / physiopathology
  • Ligation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / blood supply*
  • Neovascularization, Physiologic* / drug effects
  • RNA, Messenger / metabolism
  • Receptor, TIE-2 / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Regional Blood Flow
  • Time Factors
  • Up-Regulation
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Angiopoietin-1
  • Angiopoietin-2
  • CD11b Antigen
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Receptor, TIE-2