Angiogenesis 1997; 1; 15

NEWS AND VIEWS

Angiopoietins
Roy Bicknell
Molecular Angiogenesis Group, Imperial Cancer Research Fund, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK

There are now known to be two families of broadly endothelial specic transmembrane tyrosine kinase receptors. The rst of these are the vascular endothelial growth factor family receptors KDR and t-1, and the second comprise the Tie/Tec family. See review `Tied up (or down?) with angiopoietins' by Pamela Jones in this issue. Tie-1 and Tec (also known as Tie-2) were rst identied in 1992, and ligands for Tie and Tec have been awaited with considerable anticipation for the past 5 years. The rst ligand of Tie-2 was identied by expression cloning earlier this year and named angiopoietin. An intriguing feature of this protein is that although it stimulates Tie-2 phosphorylation in endothelial cells it is not an endothelial growth factor and neither does it stimulate endothelial cell migration. Rather, angiopoietin-1 appears to play a role in the recruitment of perivascular cells (e.g. pericytes, smooth muscle cells myocardiocytes) and elaboration of the vascular treehence the choice of the name angiopoietin. Thus, both Tie-2 and angiopoietin-1 gene knockout mice exhibit a similar vascular phenotype with poor differentiation of vascular smooth muscle and pericytes. The recent identication of a second ligand of Tie-2, named angiopoietin-2, strongly hints at the possibility of a family of angiopoietins. Neither angiopoietin-1 nor angiopoietin-2 binds to Tie-1 and identication of a ligand for this receptor is eagerly awaited. The close structural similarity between Tie-1 and Tie-2 suggests that

ligands of Tie-1 are likely to be structurally related to the angiopoietins. The story of angiopoietin-1 and angiopoietin-2 is still more intriguing, thus, although angiopoietin-2 binds to Tie-2 with an afnity comparable to that of angiopoietin-1, it also has no effect on endothelial cell proliferation or growth and unlike angiopoietin-1 does not induce Tie-2 phosphorylation. Rather angiopoietin-2 appears to be a purely competitive antagonist of angiopoietin-1 binding to Tie-2. Curiously the inhibition of Tie-2 kinase activity failed not only to block endothelial cell proliferation and angiogenesis but actually enhanced it. Research into angiopoietins is now poised to undergo a period of explosive growth. There seems little doubt that other members of the family will be rapidly identied and the characterization of a ligand for Tie-1 remains a particular prize. However, also of great interest is the cell biology of these proteins. The primary signal must originate with the Tie-2-expressing endothelial cell. Endothelial cells are known to be remarkably active cells in terms of the number of genes expressed. Angiopoiesis is in reality likely to involve a combination of release of soluble factors by the angiopoietin-1-stimulated endothelial cell combined with closely controlled adhesion molecule expression and secretion of extracellular matrix. In the fullness of time such studies will no doubt lead to a greater molecular understanding of the process known as `angiogenesis'.

Correspondence to R. Bicknell, Molecular Angiogenesis Group, ICRF, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK. Tel: (+44) 1865 222421; Fax: (+44) 1865 222431.

1997 Rapid Science Publishers

Angiogenesis Vol 1 No 1 1997

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