Using degenerate polymerase chain reaction, we isolated a cDNA encoding a novel 493-amino acid protein from human and mouse adult heart cDNAs and have designated it angiopoietin-related protein-2 (ARP2), The NH2-terminal and COOH-terminal portions of ARP2 contain the characteristic coiled-coil domain and fibrinogen-like domain that are conserved in angiopoietins, ARP2 has two consensus glycosylation sites and a highly hydrophobic region at the NH, terminus that is typical of a secretory signal sequence. Recombinant ARP2 expressed in COS cells is secreted and glycosylated, In human adult tissues, ARP2 mRNA is most abundant in heart, small intestine, spleen, and stomach. In rat embryos, ARP2 mRNA is most abundant in the blood vessels and skeletal muscles. Endothelial and vascular smooth muscle cells also contain ARP2 mRNA, Recombinant ARP2 protein induces sprouting in vascular endothelial cells but does not bind to the Tiel or TieB receptor. These results suggest that ARP2 may exert a function on endothelial cells through autocrine or paracrine action.