Developmental endothelial locus-1 (Del-1), a novel angiogenic protein: Its role in ischemia

• Published in: Circulation (New York, N.Y.) Vol. 109; no. 10; pp. 1314 - 1319
• Main Authors: HO, Hoai-Ky V, JANG, James J, KAJI, Shuichiro, SPEKTOR, Gary, FONG, Annie, YANG, Phillip, HU, Bob S, SCHATZMAN, Randy, QUERTERMOUS, Thomas, COOKE, John P
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 16.03.2004; American Heart Association, Inc
• Subjects: Angiogenic Proteins - administration & dosage; Angiogenic Proteins - physiology; Angiogenic Proteins - therapeutic use; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carrier Proteins - administration & dosage; Carrier Proteins - chemistry; Carrier Proteins - physiology; Carrier Proteins - therapeutic use; Collateral Circulation - drug effects; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Femoral Artery - surgery; Gene Expression Regulation; Hindlimb - blood supply; Injections, Intramuscular; Integrin alphaVbeta3 - physiology; Ischemia - drug therapy; Ischemia - metabolism; Magnetic Resonance Imaging; Medical sciences; Mice; Mice, Inbred C57BL; Oligopeptides - physiology; Prostheses and Implants; Vascular disease; Angiogenesis; Nervous system diseases; Ischemia; proteins; Cardiovascular disease; Locus
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000118465.36018.2D

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. 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. 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.