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  • Title: Matrix-bound sixth Ig-like domain of cell adhesion molecule L1 acts as an angiogenic factor by ligating alphavbeta3-integrin and activating VEGF-R2.
    Author: Hall H, Hubbell JA.
    Journal: Microvasc Res; 2004 Nov; 68(3):169-78. PubMed ID: 15501236.
    Abstract:
    Angiogenic signals can be matrix attached or freely diffusible. Here, the sixth Ig-like domain of L1 (L1Ig6), a ligand for alphavbeta3-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 alphavbeta3-integrin. VEGF-R2 and alphavbeta3 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 alphavbeta3. 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 alphav 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-A165. alpha5 and beta1 levels were not increased. The similarity of action of matrix-bound L1Ig6 and soluble VEGF-A165 indicate a close link between specific ligation of alphavbeta3-integrin and VEGF-R2 and suggest the possible use of matrix-bound L1Ig6 in local therapeutic angiogenesis.
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