DEVELOPMENT AND DISEASE Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels

The mechanism by which the embryonic vasculature forms can be divided into two major processes: vasculogenesis and angiogenesis. In vasculogenesis, mesodermally derived endothelial cell precursors or angioblasts migrate to future vessel sites and coalesce with neighbors to form endothelial cell cords, which lumenize and become ensheathed by supporting smooth muscle cells or pericytes. This primitive vascular network provides the substrate for angiogenic processes, which include remodeling of vasculogenic vessels, sprouting of new vessels, and intussusception, which facilitates vessel branching. A number of ligand/receptor pairs have been identified that help to coordinate vasculogenesis and angiogenesis. These include vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2); angiopoietins 1 and 2 and the Tie2 receptor; ephrin-B2 and EphB4; and platelet-derived growth factor B (PDGFB) and PDGF receptor β. Of these, only VEGF and VEGFR2 are required for both vasculogenesis and angiogenesis, whereas the rest play roles in angiogenic processes and/or perivascular sheath formation (for review, see Roman and Weinstein, 2000). TGFβ family signaling is also important in blood vessel development, although the precise ligand/receptor pairs and their specific roles are not well established. TGFβ family ligands bind to a heterodimeric complex consisting of a type II and a type I receptor, both of which are transmembrane serine/threonine kinases (for review, see Massague et al., 2000). Ligand binding stimulates the type II receptor to phosphorylate the type I receptor, which in turn phosphorylates a receptorspecific Smad. This phosphorylated Smad dimerizes with a common partner Smad (Smad4), forming a complex that translocates to the nucleus and directly regulates gene transcription. TGFβ family ligands can be divided into two groups based on Smad specificity: TGFβs, activins, and nodals signal through Smad2 and Smad3, whereas bone morphogenetic proteins (BMPs) signal through Smad1, Smad5, and Smad8. The importance of TGFβ family signaling in vessel 3009 Development 129, 3009-3019 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV14536