Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin.
Endothelial cells in growing tumors express activated Akt, which when modeled by transgenic endothelial expression of myrAkt1 was sufficient to recapitulate the abnormal structural and functional features of tumor blood vessels in nontumor tissues. Sustained endothelial Akt activation caused increased blood vessel size and generalized edema from chronic vascular permeability, while acute permeability in response to VEGF-A was unaffected. These changes were reversible, demonstrating an ongoing requirement for Akt signaling for the maintenance of these phenotypes. Furthermore, rapamycin inhibited endothelial Akt signaling, vascular changes from myrAkt1, tumor growth, and tumor vascular permeability. Akt signaling in the tumor vascular stroma was sensitive to rapamycin, suggesting that rapamycin may affect tumor growth in part by acting as a vascular Akt inhibitor.
Phung
Thuy L
TL
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Ziv
Keren
K
Dabydeen
Donnette
D
Eyiah-Mensah
Godfred
G
Riveros
Marcela
M
Perruzzi
Carole
C
Sun
Jingfang
J
Monahan-Earley
Rita A
RA
Shiojima
Ichiro
I
Nagy
Janice A
JA
Lin
Michelle I
MI
Walsh
Kenneth
K
Dvorak
Ann M
AM
Briscoe
David M
DM
Neeman
Michal
M
Sessa
William C
WC
Dvorak
Harold F
HF
Benjamin
Laura E
LE
D000818:Animals; D002199:Capillary Permeability; D002478:Cells, Cultured; D004487:Edema / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus