David BenEzra

Abstract

During the last 40 years, our understanding of the neovascular stimuli has evolved through various phases: 1. Michaelson’s postulation of an X-factor of angiogenesis in 1948 (1) remained little-noticed and unchallenged for more than two decades. 2. The demonstration of a tumor angiogenic factor (TAF) by Folkman and his group in 1971 (2) followed by the findings of a leukocyte neovascular activating factor (NAF) by BenEzra (3) and a macrophage derived angiogenic factor (MDAF) by Polverini and colleagues (4) are milestones in the search for specific factors. During the following years, a myriad of additional factors have been identified. Most widely reported are: basic and acidic fibroblast growth factors (FGF), epidermal growth factor (EGF), heparin binding growth factor (HGF), retina derived growth factor (RDGF), corneal epithelium angiogenic factor (CETAF), human uterine angiogenic factor (HUAF), endothelial cell growth factor (ECGF), tumor necrosis factor (TNF) and interleukins. All of the above factors are large peptides with a molecular weight in the range of 20,000 daltons. Additionally, a few other small molecular weight factors have been suggested. Among these, the prostaglandins, lactic acid, and endothelial stimulating angiogenesis factor (ESAF) have been studied. The multitude of angiogenic factors and their possible effect on capillary endothelial cells are schematically represented in Figure 1. 3. At present, we are on the verge of closing the cycle initiated by Michaelson’s X-factor. It is becoming more and more evident that there exists a great similarity and numerous pathways of interaction among the above identified factors. Thus, interleukin 1 (IL-1) is produced by activated leukocytes and is probably associated with NAF and MDAF. The latter is apparently identical to FGF, which may be associated with TAF, RDGF and ECGF. Furthermore, the findings of amino acid sequence homologies between FGF and IL-1 (5) reinforce my postulation made in 1978 regarding the possible identity between TAF, NAF, MDAF and Michaelson’s X-factor (6). KeywordsAngiogenic FactorCapillary Endothelial CellAmino Acid Sequence HomologyHeparin Binding Growth FactorAcidic Fibroblast Growth FactorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.