Clinical neurosciences in the decade of the brain: hypotheses in neuro-oncology. VEG/PF acts upon the actin cytoskeleton and is inhibited by dexamethasone: relevance to tumor angiogenesis and vasogenic edema.
OBJECTIVE
We have proposed that VEG/PF acts by transforming the cytoskeletal architecture of microvascular endothelial cells.


BACKGROUND
Evidence supporting a pivotal role for vascular endothelial growth/permeability factor (VEG/PF) in tumor angiogenesis and edemagenesis is compelling. VEG/PF exhibits specific endothelial cell mitogenicity and is expressed by brain tumors exhibiting increased vascularity and microvascular extravasation. The mechanistic cascade that follows VEG/PF-tyrosine kinase receptor binding remains uncertain, however. Actin is a cytoskeletal protein that regulates cellular motility, shape and vesicular transport. Regulation of actin stress fibers, cell-surface focal adhesions and plasmalemmal "ruffles" is mediated by tyrosine kinase activation of GTP-binding proteins that are in turn linked to intracellular calcium flux. As VEG/PF is known to induce cytosolic calcium ion transients in endothelial cells, actin microfilaments would appear to be logical candidates for study of a cytocontractile response mediated by calcium signal transduction.


METHODS
VEG/PF-induced endothelial actin cytoskeletal changes were studied using rhodamine phalloidin staining and fluorescence photomicrography.


RESULTS
When exposed to VEG/PF, cultured endothelial cells from human umbilical veins and rat brain microvessels exhibited a reversible, dose-related reorganization of actin stress fibers, cell contraction and rounding, and widening of the intercellular spaces. VEG/PF perturbation also induced plasmalemmal "ruffling". All VEG/PF-induced cytoskeletal changes were inhibited by preincubating endothelial cells with dexamethasone or anti-VEG/PF IgG antibody.


CONCLUSIONS
The findings support a role for VEG/PF-induced cytoskeletal alterations in the pathophysiology of brain tumor angiogenesis and edemagenesis. These observations are likely to be directly linked to VEG/PF-induced endothelial cytosolic calcium flux. Insight into the mechanism of dexamethasone's clinical efficacy is also provided.
Criscuolo
G R
GR
Yale University Medical Center, New Haven, Connecticut, USA.
Balledux
J P
JP
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects* / Q000648:ultrastructure; D003907:Dexamethasone / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005456:Fluorescent Dyes; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D010590:Phalloidine / Q000031:analogs & derivatives; D051381:Rats; D011917:Rats, Inbred Lew; D012235:Rhodamines; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005456:Fluorescent Dyes; D005938:Glucocorticoids; D008222:Lymphokines; D012235:Rhodamines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D010590:Phalloidine; D003907:Dexamethasone; D002118:Calcium