Human endothelial cells when grown in cell culture assume a "cobblestone" morphology and do not form tubes or capillarylike structures. We have recently identified a culture substrate containing basement membrane-derived proteins that promotes morphologic differentiation of human umbilical vein and human dermal microvascular endothelial cells into capillarylike tubes. This differentiation is rapid, beginning within 1 h and is complete by 8-12 h. On electron microscopy these cells form a lumen, derived from remodeling of multiple cells and also by forming holes in the cytoplasm of individual cells. The endothelial cells no longer proliferate when cultured on this substrate known as matrigel, but can be induced to do so when cultured on fibronectin. We have also identified a critical molecular signal for endothelial cell differentiation induced by matrigel. Laminin, a prime constituent of matrigel, and to lesser extent collagen IV appear to be key elements in the differentiation of endothelial cells induced by matrigel.