The aim of the study was to determine the source of vascular endothelial growth factor (VEGF) in hematoma fluid of patients suffering from chronic subdural hematoma (CSH) and to identify the level of gene expression of the pro-angiogenic factors angiopoietin 1 (ANG-1) and ANG-2 in hematoma membranes. Samples of venous blood, hematoma fluid, and outer membrane were obtained during surgery for CSH. The numbers of mononuclear cells were determined in hematoma fluid and in venous blood samples taken from 11 patients. The concentration of VEGF was measured by ELISA technique in hematoma fluid and in plasma. RT-PCR methodology was used to study the expression of different mRNA species in 11 patients. The mRNA species analyzed include VEGF and its receptors, VEGFR-1 and VEGFR-2, and ANG-1, ANG-2 and their receptor, Tie-2. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as housekeeping gene and was used for semiquantitative analysis. The VEGF concentration was several hundred fold higher in the hematoma fluid than in corresponding plasma samples. A significant correlation was found between the number of neutrophils and the VEGF content in the hematoma fluid. The expression levels of VEGF, mainly VEGF165 and VEGF121 mRNA were highest in cells obtained from the hematoma fluid. In membrane samples, mRNA encoding for VEGF and its receptors was only inconsistently detected while the mRNA species encoding for ANG-1, ANG-2, and Tie-2 were found throughout all samples. The mean ratio of ANG-1/ANG-2 mRNA expression was 0.48 as opposed to 1.9 in a normal human brain tissue sample. The results suggest that the hematoma cells are the primary source of VEGF. A marked increase in the expression of ANG-2 mRNA over ANG-1 mRNA demonstrates a pro-angiogenic pattern in the hematoma membranes. Persistent activation of the ANG/Tie-2 system in addition to high levels of VEGF may keep the vasculature in a destabilized condition and may account for the continuous formation of new and immature blood vessels resulting in massive plasma extravasation and repeated bleeding episodes. Thus, the present study provides new evidence in favor of pro-angiogenic mechanisms playing an important role in the pathophysiology of CSH.

Our data suggest that ACE-inhibitor treatment for the control of arterial hypertension lowers the risk of recurrence in patients undergoing operation for CSH and possibly even the development of CSH. This effect might be the result of an antiangiogenic mechanism of ACE-inhibitors.

Chronic subdural hematoma (CSH) is characterized by a net increase of volume over time. Major underlying mechanisms appear to be hemorrhagic episodes and a continuous exudation, which may be studied using labeled proteins to yield an exudation rate in a given patient. We tested the hypothesis that the concentration of vascular endothelial growth factor (VEGF) in hematoma fluid correlates with the rate of exudation. Concentration of VEGF was determined in 51 consecutive patients with CSH by the sandwich immune enzyme-linked immunosorbent assay technique. Mean values were correlated with exudation rates taken from the literature according to the appearance of CSH on computed tomography (CT) images. The CT appearance of each CSH was classified as hypodense, isodense, hyperdense, or mixed density. Mean VEGF concentration was highest in mixed-density hematomas (22,403±4173 pg/mL; mean±standard error of the mean; n=27), followed by isodense (9715±1287 pg/mL; n=9) and hypodense (5955±610 pg/mL; n=18) hematomas. Only 1 patient with hyperdense hematoma fulfilled the inclusion criteria, and the concentration of VEGF found in this patient was 24,200 pg/mL. There was a statistically significant correlation between VEGF concentrations and exudation rates in the four classes of CT appearance (r=0.98). The current report is the first to suggest a pathophysiological link between the VEGF concentration and the exudation rate underlying the steady increase of hematoma volume and CT appearance.With this finding, the current report adds another piece of evidence in favor of the pathophysiological role of VEGF in the development of CSH, including mechanisms contributing to hematoma growth and CT appearance.

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AXUD1-dependent apoptosis of human cementoblasts might contribute to an impaired repair of root resorptions during orthodontic tooth movement. Further studies are needed to develop treatment strategies aiming to minimize root resorption during orthodontic tooth movement.

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Unintentional reperfusion is considered a complication in various experimental models of focal brain ischemia. In the present study, we evaluated whether short intermittent reperfusion affects ischemic brain damage and blood-brain barrier (BBB) integrity in a model of permanent focal ischemia. Focal brain ischemia was induced in male Sprague-Dawley rats using the filament method. A 20-s reperfusion period was allowed 0.5, 2, or 10 min after thread occlusion of the middle cerebral artery. In control animals, the transient reperfusion episode was omitted. The infarct volume and extent of swelling was examined 24 h after permanent thread occlusion. Immunohistochemical staining for thrombin extravasation was performed. Transient reperfusion early after thread occlusion augmented brain swelling (control, 12.4 ± 8.5%; reperfusion after 0.5 min, 24.7 ± 7.0%*; after 2 min, 36.7 ± 4.8%*; after 10 min, 33.8 ± 4.9%*; *p < 0.01 vs. control) and significantly enhanced leakage of the plasma protein thrombin, whereas the ischemic volume was unaffected. Early intermittent reperfusion may be responsible for increased BBB disruption in permanent ischemia. Similar reperfusion episodes during early ischemia sequelae in patients-due to incomplete adherence or distal movements of a clot-may be causative for increased BBB damage, more severe edema, and potentially hemorrhagic transformation.

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