Vascular permeability and pathological angiogenesis in caveolin-1-null mice.
Caveolin-1, the signature protein of endothelial cell caveolae, has many important functions in vascular cells. Caveolae are thought to be the transcellular pathway by which plasma proteins cross normal capillary endothelium, but, unexpectedly, cav-1(-/-) mice, which lack caveolae, have increased permeability to plasma albumin. The acute increase in vascular permeability induced by agents such as vascular endothelial growth factor (VEGF)-A occurs through venules, not capillaries, and particularly through the vesiculo-vacuolar organelle (VVO), a unique structure composed of numerous interconnecting vesicles and vacuoles that together span the venular endothelium from lumen to ablumen. Furthermore, the hyperpermeable blood vessels found in pathological angiogenesis, mother vessels, are derived from venules. The present experiments made use of cav-1(-/-) mice to investigate the relationship between caveolae and VVOs and the roles of caveolin-1 in VVO structure in the acute vascular hyperpermeability induced by VEGF-A and in pathological angiogenesis and associated chronic vascular hyperpermeability. We found that VVOs expressed caveolin-1 variably but, in contrast to caveolae, were present in normal numbers and with apparently unaltered structure in cav-1(-/-) mice. Nonetheless, VEGF-A-induced hyperpermeability was strikingly reduced in cav-1(-/-) mice, as was pathological angiogenesis and associated chronic vascular hyperpermeability, whether induced by VEGF-A(164) or by a tumor. Thus, caveolin-1 is not necessary for VVO structure but may have important roles in regulating VVO function in acute vascular hyperpermeability and angiogenesis.
Chang
Sung-Hee
SH
Center for Vascular Biology Research and the Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Feng
Dian
D
Nagy
Janice A
JA
Sciuto
Tracey E
TE
Dvorak
Ann M
AM
Dvorak
Harold F
HF
D000256:Adenoviridae; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D051242:Caveolin 1 / Q000172:deficiency* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D012867:Skin / Q000098:blood supply / Q000473:pathology / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D051242:Caveolin 1; D042461:Vascular Endothelial Growth Factor A