This Article Full Text Full Text (PDF) All Versions of this Article: 109/10/1314    most recent 01.CIR.0000118465.36018.2Dv1 Alert me when this article is cited 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 Ho, H.-K. V. Articles by Cooke, J. P. Search for Related Content PubMed PubMed Citation Articles by Ho, H.-K. V. Articles by Cooke, J. P. Related Collections Angiogenesis Endothelium/vascular type/nitric oxide

(Circulation. 2004;109:1314-1319.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Developmental Endothelial Locus-1 (Del-1), a Novel Angiogenic Protein

Its Role in Ischemia

Hoai-Ky V. Ho, BS; James J. Jang, BA; Shuichiro Kaji, MD; Gary Spektor, BS; Annie Fong, PhD; Phillip Yang, MD; Bob S. Hu, MD; Randy Schatzman, PhD; Thomas Quertermous, MD; John P. Cooke, MD, PhD

From the Division of Cardiovascular Medicine (H.-K.V.H., J.J.J., S.K., G.S., P.Y., B.S.H., T.Q., J.P.C.), Stanford University School of Medicine, Stanford, Calif; Exelixis, Inc (A.F.), South San Francisco, Calif; and Celltech R&D, Inc (R.S.), Bothell, Wash.

Correspondence to John P. Cooke, MD, PhD, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail john.cooke{at}stanford.edu

Received May 12, 2003; revision received October 24, 2003; accepted November 18, 2003.

Background— Developmentally regulated endothelial locus-1 (Del-1) is an extracellular matrix protein that is expressed by endothelial cells during embryological vascular development. We speculated that Del-1 may be reexpressed in ischemia and may be involved in endogenous angiogenesis.

Methods and Results— Del-1 protein was detected by immunohistochemistry in murine ischemic hindlimb after femoral artery excision. To determine whether exogenous Del-1 would augment angiogenesis in vivo, Del-1 or vehicle was administered for 3 weeks by intramuscular injection of murine ischemic hindlimbs. Angiogenesis was quantified by gadolinium-MRI perfusion and capillary densitometry. We used a disc angiogenesis system (DAS) to characterize the angiogenic response to vehicle (PBS), Del-1, Del-1 mutant (altered RGD domain), Del-1 minor (truncated discoidin-I–like domain), or basic fibroblast growth factor. After 14 days, the discs were extracted and sectioned to quantify vascular growth by morphometry. Endogenous Del-1 protein expression was increased in ischemic hindlimbs. Administration of Del-1 increased hindlimb vascular flow index and capillary density. In the DAS, Del-1 doubled fibrovascular growth, as did basic fibroblast growth factor. However, angiogenesis was not enhanced by the Del-1 mutant or Del-1 minor proteins.

Conclusions— Del-1 is expressed in ischemic tissue. Del-1 stimulates angiogenesis, an effect that is dependent on the RGD motif and a second signaling sequence in the discoidin-I–like domain. Exogenous intramuscular administration of Del-1 significantly enhances angiogenesis in the murine ischemic hindlimb. Del-1 may prove to be a novel therapeutic agent for patients with ischemia.

Key Words: proteins • ischemia • angiogenesis

This article has been cited by other articles:

				E. Y. Choi, E. Chavakis, M. A. Czabanka, H. F. Langer, L. Fraemohs, M. Economopoulou, R. K. Kundu, A. Orlandi, Y. Y. Zheng, D. A. Prieto, et al. Del-1, an Endogenous Leukocyte-Endothelial Adhesion Inhibitor, Limits Inflammatory Cell Recruitment Science, November 14, 2008; 322(5904): 1101 - 1104. [Abstract] [Full Text] [PDF]

				H. Konishi, K. Sydow, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Promotes Endothelial Repair After Vascular Injury J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1099 - 1105. [Abstract] [Full Text] [PDF]

				Y. Wang, Y. Zhen, Y. Shi, J. Chen, C. Zhang, X. Wang, X. Yang, Y. Zheng, Y. Liu, and R. Hui Vitamin K Epoxide Reductase: A Protein Involved in Angiogenesis Mol. Cancer Res., June 1, 2005; 3(6): 317 - 323. [Abstract] [Full Text] [PDF]