Adenosine and hypoxia stimulate proliferation and migration of endothelial cells

The proliferation of bovine aortic or coronary venular endothelial cells (EC) in vitro was stimulated by the addition of adenosine (0.5 or 5.0 microM) to the culture medium. Cell counts of adenosine-treated aortic EC were 23-76% and coronary venular EC 19-52% greater than nontreated controls. Because adenosine is known to be released by hypoxic tissues, cell proliferation was quantitated when aortic EC were grown at 2% O2. Cell counts were 41-102% greater under hypoxic conditions than when cells were grown at standard tissue culture conditions (approximately 20% O2). When culture medium conditioned by coronary EC grown at 2% O2 was added to EC growing at standard conditions, cell counts were 24-69% greater than controls with medium conditioned by coronary EC grown at 20% O2. This suggests that hypoxia causes endothelial cells to release a factor(s) into the medium that can stimulate cell proliferation. The addition of the adenosine receptor blocker 8-phenyltheophylline (10(-5) M) prevented the stimulation of proliferation caused by hypoxia-conditioned medium, 2% O2 or 5.0 microM adenosine, suggesting that adenosine mediates its effect via an external membrane receptor. Adenosine also stimulated EC chemotaxis. Taken together, these results suggest that adenosine, released as a result of tissue hypoxia, may act as an angiogenic stimulus for the growth of new blood vessels.