Decorin regulates endothelial cell-matrix interactions during angiogenesis

Abstract

Interactions between endothelial cells and the surrounding extracellular matrix are continuously adapted during angiogenesis, from early sprouting through to lumen formation and vessel maturation. Regulated control of these interactions is crucial to sustain normal responses in this rapidly changing environment, and dysfunctional endothelial cell behaviour results in angiogenic disorders. The proteoglycan decorin, an extracellular matrix component, is upregulated during angiogenesis. While it was shown previously that the absence of decorin leads to dysregulated angiogenesis in vivo, the molecular mechanisms were not clear. These abnormal endothelial cell responses have been attributed to indirect effects of decorin; however, our recent data provides evidence that decorin directly regulates endothelial cell-matrix interactions. This data will be discussed in conjunction with findings from previous studies, to better understand the role of this proteoglycan in angiogenesis.

Acknowledgements

This manuscript is dedicated to the memory of Dr. Elke Schönherr, without whom this work would not have been possible. This work was supported by a studentship to L.F. from Cardiff University, Deutsche Forschungsgemeinschaft Grants SFB 293 and 492, SPP1086 and Eb177/5-1.

Figures and Tables

Figure 1 Decorin influences cell-matrix interactions through multiple mechanisms. Decorin signals through the IGF-IR via the core protein moiety (grey diamond), and may simultaneously interact with the α2 subunit (cross-hatched subunit) of α2β1 integrin via the GAG moiety (wavy black line) (A). Activation of Rac through IGF-IR enhances motility by modulating cytoskeleton dynamics and may influence α2β1 integrin activity for collagen I through inside-out signalling (B). Decorin induces large, peripheral vinculin (grey oval)-positive focal adhesions by signalling through IGF-IR and/or α2β1 integrin (C and D). Decorin could also directly influence α2β1 integrin activity through binding to the α2 subunit and/or simultaneous interactions with collagen I (thick wavy black line) through the core protein. Collagen I interacts with the A-domain (white circle) of the α2 subunit at a site distinct to that of decorin (D). In summary, activation of IGF-IR, Rac and modulation of α2β1 integrin affinity for collagen I by decorin modulates cell-matrix interactions and contributes to enhanced motility and tubulogenesis in a collagen I environment.

Table 1 Summary of the key functions of decorin in controlling cell behaviour