Thromboxane A 2 Receptor Agonists Antagonize the Proangiogenic Effects of Fibroblast Growth Factor-2
| Autor: | Yan Cheng, J. Anthony Ware, Armin Helisch, Anthony W. Ashton |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Integrin alphaVbeta3 Physiology Angiogenesis media_common.quotation_subject Biology Fibroblast growth factor Cell biology Endothelial stem cell Endocrinology Growth factor receptor Internal medicine Thrombospondin 1 medicine Cardiology and Cardiovascular Medicine Receptor Internalization media_common |
| Zdroj: | Circulation Research. 94:735-742 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Thromboxane (TX) A 2 is released from multiple cell types and is a prime mediator of the pathogenesis of many vascular events, including angiogenesis. Endothelial cells express TXA 2 receptors (TP) but the effects of TP stimulation on angiogenesis remain controversial. In this study, we show that stimulation of endothelial cell TP impairs ligand-induced FGF receptor internalization and consequently abrogates FGF-2-induced endothelial cell migration in vitro and angiogenesis in vivo. Prevention of FGF-2-induced angiogenesis was associated with expression of the TPβ isoform. The deficit in FGFR1 internalization was mediated through activation of TPβ preventing the FGF-2-mediated decrease in p53 expression, thus enhancing thrombospondin-1 (TSP-1) release from EC and reducing FGFR1 internalization. Once released TSP-1 interacted with the α v β 3 integrin on the EC surface. On stimulation, FGFR1 and α v β 3 were found to associate in a complex. We determined that complex formation was important for receptor internalization as conditions that inhibit FGFR1 internalization, such as inappropriate ligation of α v β 3 by either TSP-1 or a neutralizing antibody, disrupted the complex. These results establish a novel role for isoform specific regulation of angiogenesis by TP, provide the first functional significance for the existence of two TP isoforms in humans, and clarify the mechanism by which TP signaling regulates FGFR1 kinetics and signaling. |
| Databáze: | OpenAIRE |
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