TY - JOUR
T1 - The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis
AU - Ehrbar, Martin
AU - Zeisberger, Steffen M.
AU - Raeber, George P.
AU - Hubbell, Jeffrey A.
AU - Schnell, Christian
AU - Zisch, Andreas H.
N1 - Funding Information:
We thank Dr. M. Roos, Department of Biostatistics of the Medical Faculty of Zurich for consultancy, and Esther Kleiner for help with histology. This work has been supported by the European Community's Sixth Framework Programme contract (‘HeartRepair’) LSHM-CT-2005-018630. It reflects only the author's views and the Community is not liable or any use that may be made of the information contained therein. The University of Zurich has patented some of the technology described in this paper. It is being developed by Kuros Biosurgery, in which the University of Zurich and one of the authors, J.A.H., holds equity.
PY - 2008/4
Y1 - 2008/4
N2 - A major challenge for therapeutic delivery of angiogenic agents such as vascular endothelial growth factor (VEGF) is to achieve sustained, low dose signaling leading to durable neovessel formation. To this end, we recently created a variant of VEGF121, TG-VEGF121 that directly binds to fibrin and gets released locally in proteolysis-triggered manner. Here we combined noninvasive biophotonic monitoring of VEGF receptor 2 gene activation in transgenic VEGFR2-luc mice and histomorphometry to compare endothelial activation and long-term neovascularization by actively released TG-VEGF121 versus passively released, diffusible wild-type VEGF121 in subcutaneous fibrin implants. Monitoring in real-time over 3 weeks of luciferase signal driven by the VEGFR2 promoter revealed endothelial activation in skin exposed to wild-type VEGF121, but no detectable elevation over fibrin alone by TG-VEGF121. Histology at 3 weeks, however, demonstrated that TG-VEGF121 promoted vessel growth significantly more effectively and reliably than wild-type VEGF121. The majority of vessels surviving to 3 weeks contained stabilizing smooth muscle cells. Yet, by 6 weeks, no extra vessels induced by exogenous VEGF were left. In conclusion, release of fibrin-conjugated variant TG-VEGF121 elicited lower VEGFR2-luc activation than wild-type VEGF121 yet significantly more vascularization. In the absence of true physiological demand, even stabilized vessels are ultimately regressed.
AB - A major challenge for therapeutic delivery of angiogenic agents such as vascular endothelial growth factor (VEGF) is to achieve sustained, low dose signaling leading to durable neovessel formation. To this end, we recently created a variant of VEGF121, TG-VEGF121 that directly binds to fibrin and gets released locally in proteolysis-triggered manner. Here we combined noninvasive biophotonic monitoring of VEGF receptor 2 gene activation in transgenic VEGFR2-luc mice and histomorphometry to compare endothelial activation and long-term neovascularization by actively released TG-VEGF121 versus passively released, diffusible wild-type VEGF121 in subcutaneous fibrin implants. Monitoring in real-time over 3 weeks of luciferase signal driven by the VEGFR2 promoter revealed endothelial activation in skin exposed to wild-type VEGF121, but no detectable elevation over fibrin alone by TG-VEGF121. Histology at 3 weeks, however, demonstrated that TG-VEGF121 promoted vessel growth significantly more effectively and reliably than wild-type VEGF121. The majority of vessels surviving to 3 weeks contained stabilizing smooth muscle cells. Yet, by 6 weeks, no extra vessels induced by exogenous VEGF were left. In conclusion, release of fibrin-conjugated variant TG-VEGF121 elicited lower VEGFR2-luc activation than wild-type VEGF121 yet significantly more vascularization. In the absence of true physiological demand, even stabilized vessels are ultimately regressed.
KW - Biomimetic materials
KW - Fibrin
KW - Therapeutic angiogenesis
KW - Vascular endothelial growth factor
KW - VEGF receptor 2 gene activation
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U2 - 10.1016/j.biomaterials.2007.12.002
DO - 10.1016/j.biomaterials.2007.12.002
M3 - Article
C2 - 18155761
AN - SCOPUS:38749138430
VL - 29
SP - 1720
EP - 1729
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
IS - 11
ER -