In the living organism, capillary growth frequently occurs in a fibrin-rich extracellular matrix. The structure and the mechanical properties of fibrin clots are influenced by various macromolecules (i.e., hyaluronic acid and thrombospondin) and also by pH, ionic strength, and thrombin concentrations of the milieu in which they polymerize. The configuration (three-dimensional architecture) and the rigidity of fibrin clots correlate with their opacity measured by spectrophotometric absorbance readings at 350 nm. By using bovine pulmonary artery endothelial cells and bovine fibrinogen, we show here that transparent fibrin clots (A(350) < 1.0), polymerized at > or = pH 7.5 or in the presence of increased thrombin or sodium chloride concentrations, strongly stimulated capillary morphogenesis in vitro. In contrast, opaque fibrin gels (A(350) > 1.5), polymerized at pH 7.2 or in the presence of dextran, stimulated only the migration of endothelial cells but not capillary morphogenesis. We demonstrate that the angiomorphogenic effects of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are strongly dependent on the structure of the fibrin clots. Our findings suggest that bFGF/VEGF primarily stimulate the proliferation of endothelial cells, whereas the three-dimensional architecture of the fibrin matrix is decisive for capillary morphogenesis.