Expression And Significance Of CCM Genome And VEGF In Cerebral Cavernous Malformation

Background and Objective: Cerebral cavernous malformation,also known as occult vascular malformation or cavernous hemangioma,can detect one CCM lesion every 200-250 people in the general population,accounting for 5-10% of all intracranial vascular malformations.It often involves the brain and spinal cord of the central nervous system,and can also be seen in skin,liver and so on.It is composed of thin-walled and densely arranged endothelial channels,lacking smooth muscle tissue and no brain parenchyma between them.It belongs to low blood flow and low pressure vascular malformation,which occurs in vein-capillary bed.Cavernous vascular malformation of brain is familial and sporadic,and autosomal dominant inheritance is dominant in familial.There are three known pathogenic genes of cerebral cavernous malformation: KRIT1/CCM1,MGC4607/CCM2,PDCD10/CCM3.CCM gene can affect the normal angiogenesis by affecting the proliferation and migration of endothelial cells.CCM1 gene encodes KRIT1 protein,which is located in endothelial cell-cell tight junction.CCM2 gene encodes MGC4607 protein,which is involved in the formation of vascular lumen and plays a key role in the formation of CCM signal complex.CCM3 gene encodes PDCD10 protein,which affects cell connection,angiogenesis and apoptosis.In angiogenesis,the balance between promoting vascular growth factor and inhibiting vascular growth factor determines whether endothelial cells are activated.When promoting the expression of vascular growth factor more than inhibiting vascular growth factor,endothelial cells are activated and start angiogenesis.VEGF,as a kind of vascular growth promoting factor,can specifically act on vascular endothelial receptor to regulate the proliferation and migration of endothelial cells,thus affecting the development of blood vessels.VEGF is rarely expressed in normal blood vessels and is highly expressed in pathological conditions.The abnormal structure and function of KRIT1,MGC4607,PDCD10 protein or abnormal expression of VEGF caused by CCM gene mutation will change the structure and function of vascular endothelial cells,which will lead to the decrease of self-regulation ability of new blood vessels,the increase of permeability of blood vessel wall,and the formation of intracranial hemorrhage caused by blood seepage from the tube wall.The clinical manifestations of cerebral cavernous malformation are epilepsy,intracranial hemorrhage,recurrent headache and focal neurological deficit,among which intracranial hemorrhage is the main cause of clinical symptoms.Operation is the most effective way to treat cavernous malformation,but for patients with complicated conditions and high risk of operation,we need to study and find a drug that can be applied to clinical targeted treatment of cavernous malformation.In recent years,with the development of molecular biology and molecular genetics,the research on cavernous malformation is increasing,which mainly focuses on the loss of CCM gene function caused by CCM gene mutation.The mutation frequencies of CCM genome are 40% for CCM1,20% for CCM 2 and 40% for CCM3,respectively.There are few reports on cerebral cavernous malformation without gene mutation and the relationship between CCM gene coding products and VEGF expression.In this study,the expression of CCM gene coding products KRIT1,MGC4607,PDCD10 and VEGF in cerebral cavernous malformation was determined by immunohistochemistry,and the relationship between CCM genome and VEGF positive expression in cerebral cavernous malformation and its clinical significance were analyzed,which provided a theoretical basis for clinical treatment of this disease.Materials and Methods: 37 specimens of cerebral cavernous malformation,which were resected by neurosurgery from June 2017 to December 2019 in the Second Clinical Medical College of Lanzhou University,were examined by immunohistochemistry.The expression of CCM gene coding products KRIT1,MGC4607,PDCD10 and VEGF in cerebral cavernous malformation tissues was observed,and the relationship between CCM genome and VEGF positive expression in cerebral cavernous malformation and its clinical significance were analyzed.Results:Immunohistochemistry was used to detect the expression of CCM gene coding products KRIT1,MGC4607,PDCD10 and VEGF in cerebral cavernous malformation.KRIT1 was positive in 11/37 cases(29.73%),MGC4607 was positive in 7/37 cases(18.92%)and PDCD10 was positive in 9/37 cases(24.33%)The expression of VEGF was positive in 18/37 cases(48.64%),suggesting that most of the cases with positive expression of CCM1 and CCM2 were also positive.Furthermore,the correlation between CCM genome and VEGF was analyzed,and it was found that there was a significant correlation between CCM1,CCM2 and VEGF expression(P<0.05).Then,through the correlation analysis of intracranial hemorrhage,epilepsy,lesion diameter and multiple lesions with CCM genome and VEGF,it was found that the expressions of CCM1,CCM2 and VEGF in cerebral cavernous malformation with intracranial hemorrhage were higher than those in non-bleeding group,and the expressions of CCM1 and VEGF in lesion diameter > 20 mm group were higher than those in lesion diameter ≤20mm group,but there was no significant difference between epilepsy and multiple lesions and CCM genome and VEGF(P > 0.05).When analyzing the correlation among intracranial hemorrhage,epilepsy and lesion diameter,it was found that there was a significant correlation between intracranial hemorrhage and epilepsy(P<0.05),but there was no significant correlation between lesion diameter and intracranial hemorrhage and epilepsy(P > 0.05).Conclusion: 1.In cerebral cavernous malformation,CCM genome and VEGF were positively expressed in different degrees.CCM1 was 29.73%,CCM2 was 18.92%,CCM3 was 24.32%,VEGF was 48.64%;2.There is a positive correlation between CCM1 and CCM2 and VEGF expression in cerebral cavernous malformation.3.The interaction between CCM1,CCM2 and VEGF in cerebral cavernous malformation may be related to the occurrence and development of intracranial hemorrhage,and the positive expression of CCM1 and VEGF may be related to the increasing of cerebral cavernous malformation and the recurrence of lesions.