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(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

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