Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1720-1729 |
| Number of pages | 10 |
| Journal | Biomaterials |
| Volume | 29 |
| Issue number | 11 |
| DOIs | |
| State | Published - Apr 1 2008 |
| Externally published | Yes |
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Keywords
- Biomimetic materials
- Fibrin
- Therapeutic angiogenesis
- Vascular endothelial growth factor
- VEGF receptor 2 gene activation
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Biomedical Engineering
Cite this
The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis. / Ehrbar, Martin; Zeisberger, Steffen M.; Raeber, George P.; Hubbell, Jeffrey A.; Schnell, Christian; Zisch, Andreas H.
In: Biomaterials, Vol. 29, No. 11, 01.04.2008, p. 1720-1729.Research output: Contribution to journal › Article
}
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.
PY - 2008/4/1
Y1 - 2008/4/1
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
UR - http://www.scopus.com/inward/record.url?scp=38749138430&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38749138430&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2007.12.002
DO - 10.1016/j.biomaterials.2007.12.002
M3 - Article
VL - 29
SP - 1720
EP - 1729
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
IS - 11
ER -