Evaluation of the function of ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, during angiogenesis in vitro and in vivo

Abstract

Angiogenesis is required for development, growth, tissue remodeling, and wound healing. Pathologies such as diabetic retinopathy, rheumatoid arthritis and cancer would benefit from therapies controlling and reducing angiogenesis. Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They contain however some specific features, such as a variable number of domains known as “ThromboSpondin type I repeat” (TSPI). ADAMTS-1 and -8 are 20-fold more anti-angiogenic than angiostatin and endostatin, two potent inhibitors of angiogenesis. The primary function of ADAMTS-2 is the maturation of collagen type I and II molecules by excising the amino-propeptide. In addition, ADAMTS-2 could also modulate angiogenesis, as it contains the same sequences than those responsible for the anti-angiogenic activity of ADAMTS-1 and -8. This hypothesis was investigated in vitro in different experimental models such as cell proliferation and formation of capillary structures by human endothelial cells. An ex vivo angiogenesis model was also used. It consists in mice or rat aorta pieces embedded in a collagen gel in order to allow the growth of capillaries from the vascular endothelium. As compared to control mice (TS2+/+), angiogenesis was slightly increased, in absence of ADAMTS-2, from aortas of ADAMTS-2 KO mice (TS2-/-). Using rat aortas, addition of recombinant ADAMTS-2 reduced the formation of capillary structure, also confirming the anti-angiogenic activity of ADAMTS-2. Finally, an in vivo model of angiogenesis was also used. Biocompatible sponges (Ivalon) were implanted under the skin of TS2+/+ or TS2-/- mice in order to evaluate the formation of capillaries in the granulation tissue invading the sponge. In absence of ADAMTS-2, angiogenesis and granulation tissue formation were both reduced. Additional investigations are being performed in order to identify the underlying mechanism(s) inducing these modifications