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Peritumoral vasogenic brain edema (PVBE) is a common accompaniment of malignant gliomas. It results from microvascular extravasation of plasma fluid and proteins through the interendothelial spaces. Tumor-associated cysts (TACs) are observed more commonly with benign gliomas that are not associated with PVBE. This study investigates the hypothesis that these morphologically distinct epiphenomena of microvascular extravasation are linked by a common pathophysiological mechanism involving vascular endothelial growth/permeability factor (VEG/PF), which has been implicated in vascular leak phenomena including ascites, malignant effusions, and brain edema. Furthermore, VEG/PF has been isolated from cultured glioma cells, and both VEG/PF protein and messenger RNA transcripts are expressed in brain tumor tissue. To further elucidate the relationship of VEG/PF to PVBE and TACs, the authors examined 34 pathological specimens for VEG/PF expression. Nineteen primary low-grade tumors, 11 primary high-grade tumors, and four gliosis controls were immunostained with a polyclonal anti-VEG/PF immunoglobulin G antibody. Magnetic resonance imaging was used to quantitate PVBE and to determine the presence of TACs and tumor enhancement. The study revealed that eight VEG/PF-negative specimens exhibited no significant edema, whereas 26 VEG/PF-positive tumors exhibited either significant PVBE or TACs. Notably, eight of nine benign TACs that were not associated with PVBE immunostained positive for VEG/PF. These data indicate a high degree of correlation between VEG/PF expression by gliomas and the occurrence of PVBE or TACs, irrespective of tumor grade, thus supporting VEG/PF's pivotal role as the common pathophysiological link between these processes.

Metastatic brain tumors are almost always associated with vasogenic brain edema, which in turn plays a pivotal role in the evolution of neurological morbidity associated with these lesions. Attention has recently focused on a group of proteinaceous vascular permeability factors (VPF's) that are capable of inducing angiogenesis and promoting increased capillary permeability. To test the hypothesis that metastatic brain tumors expressing VPF's are associated with peritumoral cerebral edema, a rabbit polyclonal immunoglobulin (Ig) G anti-VPF was used to immunostain pathological specimens of metastatic cerebral tumors obtained from 22 patients who underwent surgery at Yale-New Haven Hospital. Magnetic resonance (MR) imaging was used to correlate VPF staining in tumor tissue with the occurrence of peritumoral brain edema. A histological study of the microvasculature was then conducted by immunostaining the specimens for endothelial cell factor VIII surface antigen, using two gliosis specimens as controls. Results revealed 21 of 22 tumors stained positively for VPF's; the negative-VPF tumor was a melanoma that exhibited no peritumoral edema. Twenty of 22 tumors had MR imaging-evident vasogenic edema. The presence and intensity of VPF immunostaining of microvascular features were noted and compared. Factor VIII staining demonstrated tumor vascularity to be most abundant in VPF-rich regions of tumor. The authors therefore report a high correlation between the presence of VPF's and the occurrence of peritumoral brain edema associated with cerebral metastases.

Serum-free conditioned medium derived from confluent monolayer cultures of malignant human astroglial tumors contains a substance that rapidly increases capillary vascular permeability after intradermal injection into guinea pigs. Accumulation of vascular permeability factor (VPF) activity occurs with increasing duration of tumor incubation in vitro. Expression of this activity is inhibited by incubation of cell cultures with cycloheximide or dexamethasone. This VPF is an acid-stable heat-labile macromolecule that is inactivated by trypsin and pepsin and binds immobilized heparin. Activity is retained by ultrafiltration with 30,000-dalton cut-off microconcentrators. Pretreatment of test animals with systemic dexamethasone prior to intradermal injection of VPF diminishes microvascular permeability. Furthermore, VPF activity is not inhibited by antihistamines. Secretion of VPF may cause the vasogenic brain edema that is frequently associated with malignant primary and metastatic intracerebral tumors. Inhibition by dexamethasone of both VPF expression in tissue culture, and VPF activity at the microvascular level in test animals, is in keeping with the known efficacy of this agent in treating the vasogenic edema associated with brain tumors.

Acute or subacute neurological deterioration without evidence of hemorrhage in a patient with a spinal arteriovenous (AV) malformation has been referred to as "Foix-Alajouanine syndrome." This clinical entity has been considered to be the result of progressive vascular thrombosis resulting in a necrotic myelopathy; it has therefore been thought to be largely irreversible and hence untreatable. The authors report five patients with dural AV fistulas who presented in this manner, and who improved substantially after embolic and surgical therapy. The outcome of these patients indicates that acute and subacute progression of myelopathy in cases of spinal dural AV fistulas may be caused by venous congestion and not necessarily by thrombosis. Therefore, a clinical diagnosis of Foix-Alajouanine syndrome is of little practical use, as spinal cord dysfunction from venous congestion is a potentially reversible process whereas thrombotic infarction is not. This diagnosis may result in suboptimal management. The recognition of nonhemorrhagic acute or subacute myelopathy as a complication of a spinal dural AV fistula is important since what appears to be irreversible cord injury is often treatable by standard surgical techniques.

A vascular permeability factor (VPF) derived from serum-free conditioned medium of cultured human malignant gliomas (HG-VPF) has been described previously. The rapid kinetics of HG-VPF activity in an in vivo assay of vascular permeability suggests a direct action upon the vascular endothelial cell. To determine whether HG-VPF was capable of inducing a physiologically significant alteration in isolated endothelial cells, cytosolic calcium [Ca++]i was measured in vitro in these cells before and after their exposure to media containing this substance. This was accomplished by preloading cultured endothelial cells with a fluorescent intracellular Ca++ probe fura-2/AM. It was found that HG-VPF induced a rapid and transient elevation of [Ca++]i in normal endothelial cells derived from human umbilical vein, bovine adrenal medulla, bovine pulmonary artery, and rat brain. This effect was inhibited by chelating extracellular calcium [Ca++]e with ethyleneglycol-bis (beta-aminoethylether)-N,N'-tetra-acetic acid (EGTA), indicating that the HG-VPF-induced response resulted from the influx of extracellular calcium. The addition of cations that act as nonspecific calcium channel blockers (Li+, Co++, Mn++, La ) completely inhibited VPF activity, further supporting the role of [Ca++]e influx. The HG-VPF activity was not, however, blocked by verapamil, a calcium antagonist that appears to be specific for voltage-gated calcium channels. Furthermore, exposure of endothelial cells to 120 mM [K+]e did not result in a calcium transient. Coincubation of endothelial cells with dexamethasone inhibited HG-VPF-induced rises in [Ca++]i, while having no effect upon cyclic nucleotide-induced changes in calcium. The present studies indicate that vascular extravasation induced by human glioma-derived VPF may be mediated by a direct action upon vascular endothelial cells. Furthermore, the observed dexamethasone-induced inhibition of this process suggests a specific cellular action for corticosteroids. This, together with previous observations that dexamethasone suppresses both the production of VPF by tumor cells in vitro and its permeability-inducing activity in vivo, may explain the efficacy of glucocorticoids in the treatment of neoplastic vasogenic brain edema. Finally, studies with a polycationic peptide (protamine) known to induce blood-brain barrier disruption in vivo revealed similar effects upon endothelial cytosolic calcium levels. As HG-VPF is a positively charged macromolecule, a common interaction between these substances and the negatively charged endothelial cell surface in the induction of permeability is suggested. Nonspecific cross-linking of charged groups of the endothelial glycocalyx and specific HG-VPF receptor binding are both valid mechanisms of HG-VPF-mediated calcium changes. Their potential relevance in the setting of microvascular permeability is discussed.

The nature of vascular permeability factor (VPF) activity derived from serum-free conditioned medium containing cultured human malignant glial tumors has been further investigated. A 1000-fold purification was accomplished by sequential heparin-Sepharose affinity chromatography and high-performance liquid chromatography gel filtration chromatography steps. Vascular permeability factor activity falls into a molecular weight range of 41,000 to 56,000 D. Activity is bound to hydroxylapatite, carboxymethyl-Sepharose, phenyl-Sepharose, and heparin-Sepharose, whereas little or no activity was bound to diethylaminoethyl-Sephacel. Vascular permeability factor activity is trypsin- and pepsin-sensitive but is unaffected by treatment with ribonuclease A. This suggests that VPF is a hydrophobic, positively charged (cationic) polypeptide with a potentially biologically significant affinity for heparin. As most proteins are negatively charged (anionic) and have no affinity for heparin, a significant advantage was gained by performing these purification steps. The activity of VPF is not inhibited by coinjection of conditioned medium with soybean trypsin inhibitor; or hexadimethrine (both known antagonists of tissue plasminogen activator, Hageman factor, and serum kallikrein); or aprotinin (an antagonist of both plasmin and tissue kallikrein); or phenylmethanesulfonyl fluoride (a serine esterase (elastase) inhibitor); or pepstatin-A (an acid protease inhibitor which inactivates vascular permeability-inducing leukokinins). These data, together with the fact that VPF is produced and released into serum-free media, provides substantial evidence against it being one of the more commonly known serum-derived permeability mediators. Treatment with dithiothreitol inhibited VPF activity, indicating the presence of at least one essential disulfide bond in this molecule. Inhibition by dexamethasone of VPF expression in cultured malignant glial cells appears to be selective. Dexamethasone-induced inhibition of VPF was dose-responsive and was not associated with a parallel inhibition of cellular protein synthesis as determined by tritiated leucine incorporation into trichloroacetic acid-precipitable material. Inclusion of dexamethasone in the culture medium was not associated with altered cell viability or cell number. A series of in vivo studies confirmed the inhibition of VPF activity in test animals pretreated with dexamethasone. This steroid-induced inhibition was partially reversed by treatment of test animals with actinomycin D prior to exposure to dexamethasone.(ABSTRACT TRUNCATED AT 400 WORDS)