Dysfunctional microvasculature as a consequence of shb gene inactivation causes impaired tumor growth.
Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed genetic background, but not on C57Bl6 mice. The present study was performed to address endothelial function in the Shb knockout mouse and its relevance for tumor angiogenesis. Tumor growth was retarded in Shb mutant mice, and this correlated with decreased angiogenesis both in tumors and in Matrigel plugs. Shb null mice display an abnormal endothelial ultrastructure in liver sinusoids and heart capillaries with cytoplasmic extensions projecting toward the lumen. Shb null heart VE-cadherin staining was less distinct than that of control heart, exhibiting in the former case a wavy and punctuate pattern. Experiments on isolated endothelial cells suggest that these changes could partly reflect cytoskeletal abnormalities. Vascular permeability was increased in Shb null mice in heart, kidney, and skin, whereas VEGF-stimulated vascular permeability was reduced in Shb null mice. It is concluded that Shb plays an important role in maintaining a functional vasculature in adult mice, and that interference with Shb signaling may provide novel means to regulate tumor angiogenesis.
Funa
Nina S
NS
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Kriz
Vitezslav
V
Zang
Guangxiang
G
Calounova
Gabriela
G
Akerblom
Björn
B
Mares
Jaroslav
J
Larsson
Erik
E
Sun
Ying
Y
Betsholtz
Christer
C
Welsh
Michael
M
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000502:physiology / Q000648:ultrastructure; D008099:Liver / Q000098:blood supply / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C085634:Shb protein, mouse; C467480:vascular endothelial growth factor A, mouse