Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice
| Autor: | Stefanie Berger, Thomas Reinheckel, H. Han, Daniel Boehringer, Gottfried Martin, Sascha Fauser, Anima Bühler, Amelie Pielen, S. Vierkotten, Andreas Stahl, Fee Bengsch, Hansjürgen Agostini, Guenther Schlunck |
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| Rok vydání: | 2013 |
| Předmět: |
Vascular Endothelial Growth Factor A
Proteases Pathology medicine.medical_specialty Angiogenesis Matrix Metalloproteinase Inhibitors Biology Cathepsin B Mice Cellular and Molecular Neuroscience Spheroids Cellular Human Umbilical Vein Endothelial Cells medicine Animals Enzyme Inhibitors Mice Knockout Cathepsin Laser Coagulation Choroid Cathepsin Z Wild type Molecular biology Choroidal Neovascularization eye diseases Sensory Systems Extracellular Matrix Mice Inbred C57BL Endothelial stem cell Disease Models Animal Ophthalmology Choroidal neovascularization Lasers Gas sense organs medicine.symptom |
| Zdroj: | Experimental Eye Research. 115:73-78 |
| ISSN: | 0014-4835 |
| DOI: | 10.1016/j.exer.2013.06.014 |
| Popis: | Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb−/−, Ctsz−/−, Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm2 vs. 0.052 mm2; p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members. |
| Databáze: | OpenAIRE |
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