The role of growth factor receptor signaling for angiogenesis and vessel stability in an experimental wound healing model
(English)Manuscript (preprint) (Other academic)
Tissue vascularization during wound healing is regulated by a variety of growth factors. Although addition of a single growth factor is sufficient to induce vascularization, at least in experimental models, the question remains on how important other endogenously produced growth factors are. We have used receptor kinase inhibitors to investigate the role of FGF-, VEGF-, PDGF- and TGFb-receptor signaling for FGF-2 and PDGF-BB induced vascularization in a wound healing model based on neovascularization of a provisional matrix implanted on the chick chorioallantoic membrane. Inhibition of the PDGF pathway with Imatinib reduced FGF-2 induced angiogenesis while FGF-receptor inhibition with PD173074 did not. FGF-2 induced angiogenesis was markedly reduced when VEGF receptors were inhibited with PTK787 as was the PDGF-BB response albeit at higher inhibitor concentrations. In agreement, sequestration of VEGF with the VEGF Trap blocked both FGF-2 and PDGF-BB induced vascularization. Inactivation of TGFbR1 with SB431542 did not influence FGF-2 or PDGF-BB induced vascularization. Higher concentrations of inhibitors did not only inhibit angiogenesis but also caused established vessels to regress. While VEGF inhibition with PTK787 mainly caused micro-vessels to regress the response to PDGF receptor inhibition with Imatinib was more profound with detachment of mural cells and regression of both micro- and macro-vessels.
In summary, we found an absolute requirement of PDGF- and VEGF-receptor signaling for wound vascularization while FGF- and TGFb-receptor signalling was dispensable. Higher concentrations of growth factor inhibitors caused vessel regression which suggests a mechanism for adverse effects such as bleedings following VEGF or PDGF inhibition in clinical settings.
Medical and Health Sciences
Research subject Medicine
IdentifiersURN: urn:nbn:se:uu:diva-113063OAI: oai:DiVA.org:uu-113063DiVA: diva2:289579