Developmental Endothelial Locus-1 (Del-1), a Novel Angiogenic Protein: Its Role in Ischemia

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

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

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-1-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-1-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.

Original languageEnglish
Pages (from-to)1314-1319
Number of pages6
JournalCirculation
Volume109
Issue number10
DOIs
StatePublished - 16 Mar 2004
Externally publishedYes

Keywords

  • Angiogenesis
  • Ischemia
  • Proteins

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