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 mm(2) vs. 0.052 mm(2); 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.