This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/11/1989    most recent ATVBAHA.108.175463v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tressel, S. L. Articles by Jo, H. Search for Related Content PubMed PubMed Citation Articles by Tressel, S. L. Articles by Jo, H.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1989.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Angiopoietin-2 Stimulates Blood Flow Recovery After Femoral Artery Occlusion by Inducing Inflammation and Arteriogenesis

Sarah L. Tressel; Hyongbum Kim; Chih-Wen Ni; Kyunghwa Chang; Juan C. Velasquez-Castano; W. Robert Taylor; Young-sup Yoon; Hanjoong Jo

From the Coulter Department of Biomedical Engineering (S.L.T., C.W.N., W.R.T., H.J.), Georgia Institute of Technology, and the Department of Medicine, Division of Cardiology (H.K., K.C., J.C.V.-C., W.R.T., Y.-S.Y., H.J.), Emory University, Atlanta, Ga.

Correspondence to Hanjoong Jo, Department of Biomedical Engineering, Emory University, WMB 2001, Atlanta, GA 30322. E-mail hanjoong.jo{at}bme.gatech.edu

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.

We investigated the role of Angiopoietin-2 in neovascularization during ischemia. We found that inhibiting Angiopoietin-2 impaired blood flow recovery during hindlimb ischemia and reduced arteriogenesis and inflammation. Angiopoietin-2 inhibition caused reduced ICAM-1 and VCAM-1 expression, resulting in reduced monocyte migration into the tissue and increased monocytes in the circulation.

Key Words: angiopoietin-2 • hindlimb ischemia • arteriogenesis • angiogenesis • inflammation

This article has been cited by other articles:

				P. Kumpers, J. Hellpap, S. David, R. Horn, H. Leitolf, H. Haller, and M. Haubitz Circulating angiopoietin-2 is a marker and potential mediator of endothelial cell detachment in ANCA-associated vasculitis with renal involvement Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1845 - 1850. [Abstract] [Full Text] [PDF]