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.

HYPOTHESIS 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. CONCLUSION 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.