In-vitro-Untersuchungen zum Wirkungsmechanismus von VEGF und seinen Inhibitoren

Zusammenfassung

Die Expression des Wachstumsfaktors VEGF und die durch ihn aktivierbaren Signaltransduktionswege sind bei der diabetischen Retinopathie dereguliert. Durch VEGF stimulierte Proliferation und Migration von Endothelzellen sowie die durch diesen Wachstumsfaktor erhöhte Permeabilität der Endothelzellen ist vorwiegend Folge seiner Bindung an den für diesen Liganden spezifischen VEGF-Rezeptor 2. Für die durch VEGF₁₆₅ induzierte Störung der Blut-Retina-Schranke ist unter Umständen die Delokalisation von Proteinen, die an der Bildung der „tight-junctions” in retinalen Endothelzellen beteiligt sind, verantwortlich. VEGF-Inhibitoren wie das VEGF-Aptamer (modifiziertes RNA-Oligonukleotid; Pegaptanib) oder spezifische Antikörper bzw. abgeleitete Fab-Fragmente (Bevacizumab, Ranibizumab), die die Interaktion von VEGF mit seinem Rezeptor beeinflussen, gelten daher als vielversprechende neue Therapeutika zur Behandlung der diabetischen Retinopathie und der altersabhängigen Makuladegeneration. In-vitro-Studien mit retinalen Endothelzellen können auch für die therapeutische Anwendung wertvolle Hinweise auf die Mechanismen der Wirkung von VEGF und seinen Inhibitoren liefern: Dabei untersucht man unter anderem den Einfluss verschiedener VEGF-Isoformen, ggf. in Kombination mit VEGF-Inhibitoren, auf Proliferation und Migration mikrovaskulärer Endothelzellen retinalen Ursprungs, sowie die Veränderung von tight-junctions nach Einwirkung von VEGF₁₆₅ und geeigneten Inhibitoren. Die in diesem Artikel neben einer Literaturübersicht enthaltenen Primärdaten stammen größtenteils aus eigenen Untersuchungen.

Abstract

VEGF expresssion and signalling are deregulated in diabetic retinopathy. Cellular processes like migration and proliferation as well as control of the permeability of the endothelium by VEGF are regulated as a consequence of its binding to the VEGF receptor 2. Proteins forming tight junctions between microvascular endothelial cells of the retina are delocated to the cytoplasm after treatment with VEGF₁₆₅, likely leading to the breakdown of the blood-retina barrier. VEGF-inhibitors such as a VEGF-aptamer (modified RNA-oligonucleotide; pegaptanib) or specific antibodies/antibody fragments (bevacizumab, ranibzumab) which directly interfere with the interaction of VEGF with its receptors are considered to be promising novel therapeutics to treat diabetic retinopathy and age-related macular degeneration. In vitro studies using microvascular endothelial cells will help to clarify the mechanisms of action of VEGF and its inhibitors. In particular, the influence of VEGF isoforms and the inhibitor ranibizumab on the proliferation and migration of bovine retinal microvascular endothelial cells was studied, as well as the rearrangement of tight-junction proteins after treatment of the cells with VEGF₁₆₅ and specific inhibitors. In addition to a review of recent publications in the field, primary data from our own studies are presented in this article.

Schlüsselwörter

diabetische Retinopathie - retinale mikrovaskuläre Endothelzellen - VEGF - VEGF-Inhibitoren

Key words

diabetic retinopathy - retinal microvascular endothelial cells - VEGF - VEGF inhibitors

Literatur

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