Cell Surface ATP Synthase: A Potential Target for Anti-Angiogenic Therapy - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 151

Fig. 9.8 Summary of the roles of ATP synthase on the surface of endothelial cells. Through its
dual roles of proton transport and ATP synthesis/hydrolysis, cell surface ATP synthase can affect
both the extracellular and intracellular environment. This enzyme complex influences the extra-
cellular levels of ATP and ADP, leading to potential downstream effects via purinergic signaling.
ATP synthase is also implicated in pH i regulation through the bidirectional movement of protons
through the transmembrane F 0 portion of the complex. The enzymatic activity of ATP synthase
on endothelial cells is regulated by several factors. Shear stress stimulates increased ATP gener-
ation by ATP synthase in HPAEC through a mechanism not yet understood. Coupling factor 6
(CF6) binds to the

subunit and stimulates ATP hydrolysis. This activity is associated with inhi-
bition of phospholipase A 2 , leading to decreased synthesis of the vasoconstrictor prostacyclin.
However, the connection between ATP hydrolysis by ATP synthase and phospholipase A 2 activ-
ity has not been elucidated. The

β

subunit of ATP synthase also acts as a receptor for endothelial
monocyte-activating polypeptide II (EMAPII), playing a partial role in the effect of this tumor-
derived cytokine on endothelial cell proliferation. The

α

subunit of ATP synthase can also affect
endothelial cell proliferation through its activity as a receptor for angiostatin. Binding of this
endogenous angiogenesis inhibitor inhibits ATP synthesis and pH i regulation by endothelial cells
under acidic conditions. It is unclear whether the anti-angiogenic effect is achieved through the
alteration in extracellular ATP levels, pH i , or a combination of both

β