Matrix-bound sixth Ig-like domain of cell adhesion molecule L1 acts as an angiogenic factor by ligating αvβ3-integrin and activating VEGF-R2

Heike Hall, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Angiogenic signals can be matrix attached or freely diffusible. Here, the sixth Ig-like domain of L1 (L1Ig6), a ligand for αvβ3-integrin, was investigated. This domain was expressed as a fusion protein having a substrate sequence for factor XIII to enable covalent binding into three-dimensional fibrin matrices. Matrix-bound L1Ig6 induced endothelial cell (EC) process extension in vitro, which was associated with ligation and phosphorylation of αvβ3-integrin. VEGF-R2 and αvβ3 were observed to co-associate after stimulation with either L1Ig6 or VEGF-A165, whereas no co-association with bFGF-R was observed. Furthermore, VEGF-R2 was tyrosine phosphorylated after stimulation with L1Ig6, even in the absence of exogenous VEGF-A165, indicating close cooperation between VEGF-R2 and αvβ3. Angiogenesis was investigated in vivo by stimulating chicken chorioallantoic membranes (CAMs) with L1Ig6-modified matrices with or without co-incorporation of VEGF-A165 or bFGF. Matrix-immobilized L1Ig6 induced angiogenesis to a similar degree as VEGF-A165; co-stimulation with bFGF increased vascular branching, whereas VEGF-A165 did not. Matrix-immobilized L1Ig6 induced up-regulation of αv in CAMs by a similar degree as stimulation with VEGF-A165, and this up-regulation was increased further by co-stimulation with matrix-bound L1Ig6 and VEGF-A 165. α5 and β1 levels were not increased. The similarity of action of matrix-bound L1Ig6 and soluble VEGF-A165 indicate a close link between specific ligation of αvβ3-integrin and VEGF-R2 and suggest the possible use of matrix-bound L1Ig6 in local therapeutic angiogenesis.

Original languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalMicrovascular Research
Volume68
Issue number3
DOIs
StatePublished - Nov 2004

Keywords

  • αvβ3-integrin
  • Angiogenesis
  • bFGF
  • CAM assay
  • Endothelial cells
  • Growth factors
  • L1Ig6
  • VEGF-A

ASJC Scopus subject areas

  • Biochemistry
  • Cardiology and Cardiovascular Medicine

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