Angiogenesis In The Formation Of Cerebral Cavernous Angioma

Background and ObjectiveCerebral cavernous angioma(CCA)is one of the common diseases in neurosurgery.Its repeated small-amount bleeding is the main problem in clinic.Intraparenchymal type of CCA could be multiple incidences and difficult to find,the imaging of dural type of CCA is usually untypical.Misdiagnosis is common upon routine imaging examinations.CCA is mainly treated by surgery,but if they are in the eloquent areas,deep brain area,brainstem and cavernous sinus,surgery could be difficult,and there is a high risk of complications.For the cases of multiple incidences,surgery is not a good option.Radiological treatment of CCA is now in its preliminary stage,and the therapeutic effects are not satisfied.The cause of CCA is not known yet.Currently,CCA is considered as a congenital disease of capillary abnormal development,about half of the patients have family history of genetic diseases.However,during patients' follow-up,de novo development of new CCA,progressive growth and recurrence after resection were found.Some investigators have demonstrated that active angiogenesis and blood vessel remodeling are presented in CCA,and hypothesized that CCA is also caused by active angiogenesis.They think inflammation,hypoxia and radiation can induce abnormal proliferation of brain blood vessel and the formation of CCA.Vascular endothelial growth factor(VEGF)and vascular endothelial growth inhibitor(VEGI)are the factors of pro-and anti-angiogenesis,respectively.The stability of blood vessels is regulated by the two important angiogenic factors.VEGF has been reported to be involved in the pathogenesis and formation of CCA,but the role of VEGI in the pathogenesis of CCA has not been elucidated yet.In this study,we investigated the pathological features,characteristics of CT/MRI images and expression of the angiogenic factors in 36 CCA cases.The aims of this study were to clarify the strategies of diagnosis and therapeutics,investigate the role of angiogenic factor in pathogenesis and formation of CCA,and identify novel targets for the conservative treatment for the patients that are not suitable of surgery.MethodsIn this study,data from 36 cases of CCA and 15 cases of normal control were investigated.CT/MRI images from 36 CCA cases were retrospectively analyzed,the HE staining of the CCA specimen and the ultrastructure of 2 cases were summarized,misdiagnostic rate upon imaging before surgery were calculated,and the specificities of the CT and MRI diagnosis were compared.Using immunohistochemistry staining,the expressions of VEGF and VEGI were examined and compared between CCA and normal control cases.ResultsUnder microscope,the pathology of CCA are composed of dilated,thin-walled capillaries that is lined up with only mono-layer of endothelia and a thin basal membrane.Elastic fibers and smooth muscles are absent in the walls of these vascular caverns.Thrombosis and calcification may present within some of the lumens.Almost all the cases exhibit old or new bleeding,precipitation of hemosiderin and proliferation of colloid.Under electron microscope,the blood vessels are lined up with monolayer of endothelia.There is no tight-conjunctions between endothelia.Bleeding effusions are visible.Basal membranes are not clear,large amount of collagenous fibers and high electronic density sediments of cell debris could be seen.Imaging diagnosis:for the 5 cases examined only by CT,the noncoincidence between imaging and pathological diagnosis is 100%,the specificity of diagnosis is 0;for the 6 cases examined only by MRI,the noncoincidence between imaging and pathological diagnosis is 33.3%,the specificity of diagnosis is 66.7%;for the 25 cases examined by both CT and MRI,the noncoincidence between imaging and pathological diagnosis is 8.0%,the specificity of diagnosis is 92.0%.According to the statistical analysis,MRI only and CT/MRI combined examinations are significantly better than the CT only examination(p<0.01);while,the examinations between MRI only examination and CT/MRI combination have no significant difference(p>0.05).Immunohistochemistry staining:The positive expressions of Von Willebrand factor(vWF)between CCA and normal control groups are 86.67%and 86.11%,respectively,and are not significantly different(p>0.05).The positive expressions of VEGF between CCA and normal control groups are 58.33%and 6.67%,respectively,and are significantly different(p<0.01).The positive expressions of VEGI between CCA and normal control groups are 0%and 100%,respectively,and are significantly different(p<0.01).The relative positive expressions of VEGF are 23.85±7.10%and 1.99± 1.30%,respectively between CCA and normal control groups,which is significantly different(p<0.05).The relative positive expressions of VEGI are 0%and 38.36±5.45%,respectively between CCA and normal control groups,which is significantly different(p<0.01).Conclusion1.The pathological characteristics of CCA are repeated small-mount bleeding,thromboses,calcification,deposit of hemosiderin and proliferation of colloid,which may contribute to the progressive growth of CCA.2.The pathogenesis of repeated hemorrhage is that the blood vessels are lined up with only monomayer of endothelia,lack of the support of fiber and muscle,no tight-junction between endothelia.Repeated hemorrhage is the pathogenesis of clinical symptom and MRI images.3.Diagnosis of CCA:MRI has a higher specificity over CT.combination of CT and MRI elevates the accuracy of diagnosis4.The imbalance of pro-and anti-angiogenic factors,i.e.,down-regulation of VEGI and up-regulation of VEGF,could be one of the key reasons in the formation and progression of CCA.VEGI could be considered as a novel target in the prevention and therapeutics of CCA.