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Issue 9, 2011
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VEGF internalization is not required for VEGFR-2 phosphorylation in bioengineered surfaces with covalently linked VEGF

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Abstract

Vascular endothelial growth factor (VEGF) is known to activate proliferation, migration, and survival pathways in endothelial cells through phosphorylation of VEGF receptor-2 (VEGFR-2). VEGF has been incorporated into biomaterials through encapsulation, electrostatic sequestration, and covalent attachment, but the effect of these immobilization strategies on VEGF signaling has not been thoroughly investigated. Further, although growth factor internalization along with the receptor generally occurs in a physiological setting, whether this internalization is needed for receptor phosphorylation is not entirely clear. Here we show that VEGF covalently bound through a modified heparin molecule elicits an extended response of pVEGFR-2 in human umbilical vein endothelial cells (HUVECs) and that the covalent linkage reduces internalization of the growth factor during receptor endocytosis. Optical tweezer measurements show that the rupture force required to disrupt the heparin–VEGF–VEGFR-2 interaction increases from 3–8 pN to 6–12 pN when a covalent bond is introduced between VEGF and heparin. Importantly, by covalently binding VEGF to a heparin substrate, the stability (half-life) of VEGF is extended over three-fold. Here, mathematical models support the biological conclusions, further suggesting that VEGF internalization is significantly reduced when covalently bound, and indicating that VEGF is available for repeated phosphorylation events.

Graphical abstract: VEGF internalization is not required for VEGFR-2 phosphorylation in bioengineered surfaces with covalently linked VEGF

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Publication details

The article was received on 24 Apr 2011, accepted on 08 Jul 2011 and first published on 08 Aug 2011


Article type: Paper
DOI: 10.1039/C1IB00037C
Citation: Integr. Biol., 2011,3, 887-896
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    VEGF internalization is not required for VEGFR-2 phosphorylation in bioengineered surfaces with covalently linked VEGF

    S. M. Anderson, B. Shergill, Z. T. Barry, E. Manousiouthakis, T. T. Chen, E. Botvinick, M. O. Platt, M. L. Iruela-Arispe and T. Segura, Integr. Biol., 2011, 3, 887
    DOI: 10.1039/C1IB00037C

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