A similar argument can be used in cases of training or chronic stimulation where the tissue PO, values were either normal or elevated. It is also conceivable that a lack of oxygen per se would not stimulate capillary growth in vivo but could lead to the release of metabolites, such as lactate or adenosine, or result in a lower pH that could trigger activation of other factors involved in capillary growth.Lactate also stimulated the growth of vessels on chicken chorioallantoic membrane. How ever, muscles stimulated at a low frequency with capil lary growth had a lower lactate concentration than con trol muscles, whereas high concentrations of lac tate were found in skeletal muscles stimulated chronically at a high frequency and preceded capillary growth. This may indicate that lactate is not involved in capillary growth under these conditions, but it still remains to be determined whether increased lac tate concentration, and thus decreased pH, would pre cede capillary growth in muscles stimulated at low fre quency.In CAM, ADP stimulated the growth of vessels and also the growth of endothe lial cells Argatroban derived from bovine aorta but not the growth of capillaries in tissue culture suggested a role of ADP in migration, rather than mitotis, of endothelial cells in vitro.Adenosine accumulates in hypoxic hearts and is the most important factor involved in the mediation of coro nary vasodilatation, but its direct involve ment in capillary growth either in the heart or in skele tal muscles has yet to be demonstrated.The amount of adenosine in chronically stimulated muscles at the time when capillaries started to grow was lower than in con trol muscles. Recently, bradykinin was shown to have a possible mitogenic role in fibroblasts. Schoefl suggested that mast cells and hista mine are involved in capillary growth in injury.Hista mine stimulated vessel growth on CAM as well as the growth of endothelial cells in tissue cultures. Mast cells also contain heparin and neutral proteases, of which the latter can loosen cell attachment and stimu late capillary growth. Heparin has a very impor tant role in angiogenesis, since many growth factors are bound to it. Their effects have been Everolimus studied primarily in vitro on endothelial cells of different origins, smooth muscle cells, or fibroblasts and in vivo in rabbit cornea, CAM, or various implanted chambers to give just a few examples.The role of various growth factors in angiogenesis has recently been the subject of several reviews. They also seem to be the most important factors involved in angiogenesis, al though lowmolecularweight and synovial fluid. Angiogenic factor, whose activity was tested on CAM, was found in extracts from onehalf of the control rabbit hearts but in every sample of bradycardially paced hearts showing capillary proliferation.In con trast, its presence was similar in muscles with capillary growth induced by chronic electrical stimulation as in control muscles, from chick embryonic cardiac and skeletal muscle, as well as from cultured chick em bryonic and adult human muscle cells that FGF can be in volved in the growth of collaterals in porcine heart, its possible role in capillary growth in skeletal muscle needs further elucidation.