Cellular fibronectin (FN) and tenascin-C (TNC) are prominent development-and disease-associated matrix components with pro-and anti-adhesive activity, respectively. Whereas both are present in the tumour vasculature, their functional interplay on vascular endothelial cells remains unclear. We have previously shown that basally-oriented deposition of a FN matrix restricts motility and promotes junctional stability in cultured endothelial cells and that this effect is tightly coupled to expression of FN. Here we report that TNC induces FN expression in endothelial cells. This effect counteracts the potent anti-adhesive activity of TNC and leads to the assembly of a dense highly-branched subendothelial matrix that enhances tubulogenic activity. These findings suggest that pro-angiogenic remodelling of the perivascular matrix may involve TNC-induced upregulation of FN in endothelial cells. Angiogenesis, the sprouting of new vasculature from a pre-existing vascular network, is an essential process during development, maintenance of tissues and metastatic spread of cancer. This multi-step process is tightly regulated and spatiotemporally controlled by various soluble cytokines, membrane-bound proteins, cell-matrix and cell-cell interactions and hemodynamic forces. In recent years it has become clear that dynamic remodelling of the extracellular matrix (ECM) is essential for all stages of angiogenesis. Through adhesive interactions with integrins expressed on the endothelial cell surface, the ECM orchestrates complex signalling cascades within the cells and affects many fundamental aspects of their biology, including proliferation, migration, cytoskeletal organization, cell shape, survival, and ultimately blood vessel stabilization (reviewed in 1). Tenascin-C (TNC) and alternatively spliced forms of fibronectin (FN) are principle ECM components of the angiogenic vasculature of tumours, yet barely detected in quiescent adult vessels (reviewed in 2). Genetic studies in mice and fish have pointed to a fundamental role for FN and its primary receptor α5β1 integrin in early blood vessel development and vascular physio-pathology (reviewed in 3,4). FN-null mice die at embryonic day 9.5 with severe cardiovascular defects 5 and α5 null mice display the most severe vascular defects of all the null phenotypes of α-encoding inte-grin genes 6. Although TNC knockout mice do not display an embryonic lethal phenotype 7,8 , TNC expression is highly associated with angiogenesis in a wide range of disease states, including cancer 9–11. Adhesive and counter-adhesive effects are attributed respectively to FN and TNC. One mechanism by which TNC modulates cell adhesion-dependent processes involves its direct interaction with FN, which leads to interference of FN binding to syndecan-4 12. TNC can also interact with cognate integrins on the surface of cells 13 (and references therein). Endothelial cells express TNC-binding integrin αvβ3 3. αvβ3 is upregulated in tumour-associated blood vessels where it has been found to play both pro-and anti-angiogenic roles in tumour angiogenesis, depending on the context 14. FN matrix assembly, or fibrillogenesis, is a complex process (reviewed in 15,16) driven by α5β1 integrin that takes place at specialized integrin-based structures called fibrillar adhesions at the cell-matrix interface