Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-3076
Ehrbar, M; Zeisberger, S M; Raeber, G P; Hubbell, J A; Schnell, C; Zisch, A H (2008). The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis. Biomaterials, 29(11):1720-1729.
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 VEGF(121), TG-VEGF(121) 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-VEGF(121)versus passively released, diffusible wild-type VEGF(121) 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 VEGF(121), but no detectable elevation over fibrin alone by TG-VEGF(121). Histology at 3 weeks, however, demonstrated that TG-VEGF(121) promoted vessel growth significantly more effectively and reliably than wild-type VEGF(121). 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-VEGF(121) elicited lower VEGFR2-luc activation than wild-type VEGF(121) yet significantly more vascularization. In the absence of true physiological demand, even stabilized vessels are ultimately regressed.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Center for Dental Medicine > Clinic for Cranio-Maxillofacial Surgery|
04 Faculty of Medicine > University Hospital Zurich > Clinic for Obstetrics
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||09 Sep 2008 06:37|
|Last Modified:||27 Nov 2013 17:40|
|Citations:||Web of Science®. Times Cited: 60|
Scopus®. Citation Count: 57
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