The angiopoietins have recently joined the members of the vascular endothel
ial growth factor family as the only known growth factors largely specific
for vascular endothelium. The angiopoietins include a naturally occurring a
gonist, angiopoietin-1, as well as a naturally occurring antagonist, angiop
oietin-2, both of which act by means of the Tie2 receptor. We now report ou
r attempts to use homology-based cloning approaches to identify new members
of the angiopoietin family. These efforts have led to the identification o
f two new angiopoietins, angiopoietin-3 in mouse and angiopoietin-3 in huma
n; we have also identified several more distantly related sequences that do
not seem to be true angiopoietins, in that they do not bind to the Tie rec
eptors. Although angiopoietin-3 and angiopoietin-4 are strikingly more stru
cturally diverged from each other than are the mouse and human versions of
angiopoietin-1 and angiopoietin-2, they appear to represent the mouse and h
uman counterparts of the same gene locus, as revealed in our chromosomal lo
calization studies of all of the angiopoietins in mouse and human. The stru
ctural divergence of angiopoietin-3 and angiopoietin-4 appears to underlie
diverging functions of these counterparts. Angiopoietin-3 and angiopoietin-
4 have very different distributions in their respective species, and angiop
oietin-3 appears to act as an antagonist, whereas angiopoietin-4 appears to
function as an agonist.