Aminopeptidase A is a functional target in angiogenic blood vessels.
We show that a membrane-associated protease, aminopeptidase A (APA), is upregulated and enzymatically active in blood vessels of human tumors. To gain mechanistic insight, we evaluated angiogenesis in APA null mice. We found that, although these mice develop normally, they fail to mount the expected angiogenic response to hypoxia or growth factors. We then isolated peptide inhibitors of APA from a peptide library and show that they specifically bind to and inhibit APA, suppress migration and proliferation of endothelial cells, inhibit angiogenesis, and home to tumor blood vessels. Finally, we successfully treated tumor-bearing mice with APA binding peptides or anti-APA blocking monoclonal antibodies. These data show that APA is a regulator of blood vessel formation, and can serve as a functional vascular target.
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Serena
S
Marchiò
Johanna
J
Lahdenranta
Reinier O
RO
Schlingemann
Donatella
D
Valdembri
Pieter
P
Wesseling
Marco A
MA
Arap
Amin
A
Hajitou
Michael G
MG
Ozawa
Martin
M
Trepel
Ricardo J
RJ
Giordano
David M
DM
Nanus
Henri B P M
HB
Dijkman
Egbert
E
Oosterwijk
Richard L
RL
Sidman
Max D
MD
Cooper
Federico
F
Bussolino
Renata
R
Pasqualini
Wadih
W
Arap
D020816:Amino Acid Motifs; D000818:Animals; D001808:Blood Vessels; D002455:Cell Division; D015687:Cell Hypoxia / Q000502:physiology; D002465:Cell Movement; D002642:Chick Embryo; D042783:Endothelial Cells / Q000502:physiology*; D004791:Enzyme Inhibitors; D043384:Glutamyl Aminopeptidase / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism; D009389:Neovascularization, Pathologic; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D014183:Transplantation, Heterologous / Q000473:pathology
D004791:Enzyme Inhibitors; D006133:Growth Substances; D019151:Peptide Library; D010455:Peptides; D043384:Glutamyl Aminopeptidase