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


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.
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif, USA.
Hoai-Ky V
HK
Ho
James J
JJ
Jang
Shuichiro
S
Kaji
Gary
G
Spektor
Annie
A
Fong
Phillip
P
Yang
Bob S
BS
Hu
Randy
R
Schatzman
Thomas
T
Quertermous
John P
JP
Cooke
D042501:Angiogenic Proteins / Q000008:administration & dosage / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000502:physiology* / Q000627:therapeutic use; D015815:Cell Adhesion Molecules; D003097:Collateral Circulation / Q000187:drug effects*; D005260:Female; D005263:Femoral Artery / Q000601:surgery; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply*; D007273:Injections, Intramuscular; D039302:Integrin alphaVbeta3 / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000502:physiology; D019736:Prostheses and Implants
D042501:Angiogenic Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C491706:Edil3 protein, mouse; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid