Angiogenesis plays a critical role in the normal development of higher eukaryotic organisms.
It is also widely accepted to play an important role in normal physiologic processes of adult organisms such as female reproduction, wound healing, and collateral blood vessel formation in some ischemic conditions, and in the sequelae of pathologic processes such as diabetic retinopathy, atherosclerosis, psoriasis, and rheumatoid arthritis, and tumor angiogenesis. One such RTK, Tie-2 has been demonstrated to be necessary for developmental angiogenesis, and animal and human studies suggest that it plays an important role in regulating tumor angiogenesis. Among RTKs, Tie-2 is unusual in that it has multiple ligands that differentially modulate its activity, and therefore differentially modulate its effects on angiogenesis. The first of these directions is being investigated through molecular dissection of the structural and functional domains of Ang1 and Ang2 to characterize the mechanisms by which they bind and modulate Tie2 activity. To understand the physiological functions of the angiopoietins, we are examining their roles in tumor angiogenesis and in an in vivo model of neoangeogenesis in mice.