Matricellular proteins are macromolecules located in the extracellular matrix (ECM) that participate in a variety of cellular functions including cell migration, adhesion and proliferation but do not contribute to ECM structure themselves. Secreted modular calcium-binding protein 1 (SMOC-1) is a matricellular protein and has been shown to be a transforming growth factor (TGF) β antagonist. Given that, depending on the cellular context, TGFβ can either promote or inhibit angiogenesis we set out to determine the role of SMOC-1 in angiogenesis.

SMOC-1 was expressed by endothelial cells and its expression was upregulated by interleukin-1β, TGFβ, tumor necrosis factor 1α and hypoxia, but decreased by shear stress in a KLF2-dependent manner. Functionally, knockdown of SMOC-1 (siRNA) prevented proliferation, migration and the integrin-dependent adhesion of HUVEC on collagen- and laminin. The loss of SMOC-1 also impaired endothelial cell tube formation and sprouting in vitro (modified spheroid assay) and ex vivo (aortic rings from SMOC-1^+/- mice). In vivo cell infiltration (of CD45+ cells) into Matrigel plugs was increased after 3 days in the presence of SMOC-1 and showed more prominent angiogenesis after another 7 days. In accordance, vascularisation in Matrigel and retinal angiogenesis in SMOC-1^+/- mice was attenuated. Mechanistically, the expression of SMOC-1 decreased TGFβ reporter gene construct activity and the knockdown of SMOC-1 reduced integrin α2 expression in human endothelial cells.

In summary, SMOC-1 is a secreted molecule regulated by KLF2 and hypoxia and important for endothelial cell homeostasis by modulating TGFβ signalling and thereby affecting angiogenic processes.