European Journal of Clinical Investigation (2004) 34, 9–13 © 2004 Blackwell Publishing Ltd Blackwell Science, Ltd Hypothesis Angiopoietin/tie-2 as mediators of angiogenesis: a role in congestive heart failure? A. Y. Chong, G. J. Caine and G. Y. H. Lip Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK Abstract Angiogenic factors, in particular vascular endothelial growth factor ( VEGF) and the angio- poietins, Ang-1 and -2, have recently generated significant interest, especially in oncology. The process of angiogenesis is also thought to occur in response to ischaemic conditions, which lie at the core of cardiovascular disease states such as coronary artery disease and congestive heart failure. However, current data do not conclusively show evidence of angio- genesis per se in these conditions, despite (for example) the presence of high levels of VEGF and Ang-2. High levels of these angiogenic factors in heart disease also have not translated into clinically significant new vessel formation, as in accelerated cancer growth or proliferative retinopathy. Indeed, we would hypothesize that these angiogenic markers – especially the angiopoietins – do not necessarily translate into new vessel formation in congestive heart failure (CHF), but may well reflect disturbances of endothelial integrity in CHF. Keywords Angiogenesis, angiopoietin, congestive heart failure, vascular endothelial growth factor. Eur J Clin Invest 2004; 34 (1): 9–13 Introduction Angiogenesis is defined as the sprouting and growth of new vessels, as well as the branching and extension of existing capillaries by the assembly of endothelial cells (ECs) from pre-existing vessels to form new capillaries networks [1]. In contrast, the process of arteriogenesis is defined as the growth, development and remodelling of pre-existing vessels, mainly arterioles that form the collateral system [2]. As almost all functional cells are located within 30 μm of a blood capillary, angiogenesis and arteriogenesis are mandatory processes that ensure cell survival. Angiogenic factors, in particular vascular endothelial growth factor ( VEGF) and the angiopoietins, Ang-1 and -2, have recently generated significant interest, especially in oncology. Indeed, these angiogenic factors are prerequisite for tumour growth and correlate with worse prognosis.There are also studies on the role of VEGF, but not angiopoietins, in myocardial ischaemia, but large studies on angiogenesis in relation to associated disorders that have elements of endothelial dysfunction and tissue hypoxia, such as conges- tive heart failure (CHF), are lacking. Preliminary data show that plasma VEGF and Ang-2, but not Ang-1, levels are elevated in CHF [3,4], possibly supporting the hypothesis of angiogenesis occurring in CHF. However, we would hypothesize that these angiogenic markers – especially the angiopoietins – do not necessarily translate into new vessel formation in CHF, but may well reflect disturbances of endothelial integrity in CHF. Angiopoietin / tie-2 system Four members of the angiopoietin family have been identified to date. Angiopoietin-1 and -2 have been studied in more detail and are thought to play a role in angiogenesis. Experiments show that neither Ang-1 nor Ang-2 stimulates proliferation of endothelial cells (ECs) on their own, and that their roles are modulatory in the presence of VEGF [5]. The exact roles of Ang-3 and -4, on the other hand, remain undefined. Angiogenic-3, a tie-2 receptor antagonist, appears Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK (A. Y. Chong, G. J. Caine, G. Y. H. Lip). Correspondence to: Professor G.Y.H. Lip, Haemostasis,Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, B18 7QH, UK. Tel.: 0121 5075080; fax: 0121 5544083; e-mail: g.y.h.lip@bham.ac.uk Received 17 September 2003; accepted 3 November 2003