Cell Surface ATP Synthase: A Potential Target for Anti-Angiogenic Therapy - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 135

Chapter 9
Cell Surface ATP Synthase: A Potential Target
for Anti-Angiogenic Therapy

Yvonne M. Mowery and Salvatore V. Pizzo

Abstract Since the presence of F 1 F 0 adenosine triphosphate (ATP) synthase was
discovered on the surface of human cells, numerous studies have elucidated new
functions for this molecule that classically functions as part of the electron transport
chain in mitochondria. Like mitochondrial ATP synthase, the cell surface form of
this molecule functions as an energy-producing proton pump, coupling the produc-
tion of extracellular ATP with the transport of protons outside the cell. ATP synthase
also acts as an endothelial cell surface receptor for angiostatin, which has led sev-
eral groups to examine this molecule as a target for inhibiting angiogenesis. Given
its involvement in proton transport and the pH-dependent activity of angiostatin and
antibodies directed against it, ATP synthase likely functions in part to regulate pH
for endothelial cells existing in an acidic microenvironment. In addition, it catalyzes
the synthesis and hydrolysis of ATP in the extracellular milieu, potentially affecting
purinergic signaling. ATP synthase also plays a role in endothelial cell signaling
in response to flow-induced shear stress. Recently, ATP synthase on the surface of
endothelial cells has been identified as the receptor for two additional proteins: cou-
pling factor 6 and endothelial monocyte-activating polypeptide II. This chapter will
focus on the role of endothelial cell surface ATP synthase in angiogenesis, shear
stress response, and as a receptor.

Keywords Cell surface ATP synthase · Alpha subunit of ATP synthase · Beta

subunit of ATP synthase · Endothelial cell · Angiostatin · Angiogenesis · Anti-

angiogenic treatment · ATP synthesis · ATP hydrolysis · Purinergic signaling · pH

regulation · Coupling factor 6 · Shear stress · Endothelial monocyte-activating

polypeptide II · Heparan sulfate · Caveolae · Sangivamycin · Monoclonal antibody

therapy

B

Y.M. Mowery ( )

Department of Pathology, Duke University, DUMC Box 3712, Durham, NC 27710, USA
e-mail: [e-mail]