Mikro- und Nano- Computertomographie zur ex-vivo Evaluation von Neoangiogenese nach Sinusthrombose am Tiermodell

Abstract

Cerebral vein and sinus thrombosis (CVST) is generally regarded rare. It is a disease which predominantly affects children and young adults. The median age of adult cases is 35-40 years. In adulthood, more than two thirds of cases are females. However, with non-invasive imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) angiography it has become clear that CSVT is by far more frequent than previously thought. Although the true incidence in the general population is not known, the frequency of CSVT in patients with subacute headache of increasing intensity with or without signs of raised intracranial pressure, or headaches in combination with focal neurological deficits, seizures or disturbed consciousness is about 10%. Approximately 50% of patients develop venous brain infarcts which frequently are hemorrhagic. Recanalization has been frequently observed in the early phase of CSVT, but it seems to have no influence on the functional clinical outcome, neither does persistent occlusion. Venous infarcts differ in their behaviour from arterial stroke. Even large MRI-detectable lesions completely resolve over time in more than 50% of patients. Although infarcts resolve faster in patients with early recanalization, the final infarct volume is not influenced by recanalization or persistent occlusion. This may be caused either by adaptation of venous collaterals to the higher flow demand, or by angiogenesis, or by both. An other indication that CSVT might induce angiogenesis is the development of dural arterio-venous fistulas (DAVF) as a complication of the disease. Still it is unclear to what extent CSVT induces angiogenesis, how the venous angioarchitecture is affected, and whether angiogenesis is effective by relieving venous congestion in the upstream cortical veins proximal to the occlusion. This study examines angiogenesis in a standardized, non-lethal rat model of persistent superior sagittal sinus (SSS) thrombosis. This model allows for standardization of the time of onset and control of physiological variables not possible in human case series. We used micro- and nano-CT to study the venous vascular changes and demonstrate Neoangiogenesis as the main reason for the good clinical outcome and the reduced final infarct volume . These techniques have the advantage that three-dimensional quantification of structural properties of microvascular networks is possible. In this study we were able to demonstrate neoangiogenesis 6 weeks after thrombus induction within the lumen of the thrombosed SSS as a network of small venules which connect to cortical veins. These newly formed vessels coincide with the locally strong VEGF expression in the organized thrombus consistent with neoangiogenesis. This process is so effective, that the cross-sectional area of contrast filling within the original lumen of the SSS is significantly larger than in control animals. The most important finding is an increase of the cortical venous volume fraction above control levels after 6 weeks, although only traces of VEGF expression could be found in the parasagittal region. The imaging techniques applied in this study are recently developed imaging tools which allow image resolution in the micrometer and submicron-resolution range. In conclusion we were able to show in this model of non-lethal permanent superior sagittal sinus thrombosis the organization of the thrombus by angiogenesis. Beyond that we observed venogenesis in form of an increased cortical venous volume fraction and large transcortical veins remote from the thrombus itself.