VEGF-Functionalized Dextran Has Longer Intracellular Bioactivity than VEGF in Endothelial Cells

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• 作者：Jo茫o Maia ; Helena Vaz茫o ; Dora C. S. Pedroso ; Catarina S. H. Jesus ; Rui M. M. Brito ; M谩rio Gr茫os ; Maria H. Gil ; Lino Ferreira
• 刊名：Biomacromolecules
• 出版年：2012
• 出版时间：September 10, 2012
• 年：2012
• 卷：13
• 期：9
• 页码：2906-2916
• 全文大小：551K
• 年卷期：v.13,no.9(September 10, 2012)
• ISSN：1526-4602

文摘

Herein, we report that VEGF-functionalized dextran (dexOx-VEGF) is comparatively superior to free VEGF in prolonging the phosphorylation of VEGF receptor 2 (VEGFR-2). Both dexOx-VEGF and free VEGF activate VEGFR-2, and the complexes are internalized into early endosomes (EEA1⁺ vesicles) and then transported to lysosomes (Rab7⁺ vesicles). However, after cell activation, dexOx-VEGF is preferentially colocalized in early endosomes where VEGF signaling is still active while free VEGF is preferentially transported to late endosomes or lysosomes. We further show that dexOx-VEGF after phosphorylation of VEGF receptor 2 induces an increase of intracellular Ca²⁺ and activates VEGF downstream effectors such as Akt and extracellular signal-regulated kinase (ERK1/2) proteins. Under specific conditions, the activation level is different from the one observed for free VEGF, thus suggesting mechanistic differences, which is illustrated by cell migration and cord-like formation studies. DexOx-VEGF can be cross-linked with adipic acid dihydrazide to form a degradable gel, which in turn can be incorporated in a fibrin gel containing endothelial cells (ECs) to modulate their activity. We envision that these constructs might be beneficial to extend the pro-angiogenic activity of VEGF in ischemic tissues and to modulate the biological activity of vascular cells.