Correlation Analysis Between The Expression Of VEGF And DLL4 In Brain Arteriovenous Malformationn Of Vascular Endothelial Cells And Hemodynamics

Objective:Brian arteriovenous malformation is a congenital disease, is the brian vascular variation in the process of embryonic development. The local capillary dysplasia in early embryo, causes the artery and vein connected directly. With artery blood flowing into the vascular malformation,it leads to a series changes of brian hemodynamics, which cause clinical symptoms.The study found that there is interaction between the antivascular endothelial growth factor and vascular growth factor to regulate the process of angiogenesis, in which vascular endothelial growth factor(VEGF) and DLL4-Notch signal transduction pathway involved. Studies show that vascular endothelial growth factor(VEGF) is the main growth factor on angiogenesis, promoting the vascular permeability increasing, vascular endothelial cell spliting, and proliferating, which is particularly expressed in vascular endothelial cells. Previous studies indicate that Notch signaling pathway plays an important role in the process of embryonic development and vascular formation. DLL4 is the main ligand of Notch receptor, and is confirmed an important downstream gene of VEGF, which can limit the vessel excessive growth through a negative feedback on VEGF. Both DLL4 and VEGF are involved in the regulation of vascular growth. brian arteriovenous malformation group lead to the hemodynamics changed, making the relative hypoxia environment around the brain tissue, which causes the tissues to secrete corresponding vascular endothelial growth factor, to promote the angiogenesis and remodeling. The expression of DLL4 and VEGF, the interaction between them and the hemodynamic changes, all will affect the angiogenesis and then influence the occurrence and development of brian arteriovenous malformation vascular mass, and the specific mechanism is still unknown in them. By detecting the expression of VEGF and DLL4 in different hemodynamic state of abnormal vascular mass, investigate the relevance between the expression level of VEGF, DLL4 and the hemodynamics in brian arteriovenous malformation vascular mass, to analysis the different expression of VEGF, DLL4 in brian arteriovenous malformation vascular mass and provide experimental and theoretical basis for clinical diagnosis and treatment, and even put up a new treatment concept.Methods: Selected the 40 pathological paraffin embedded tissue sections of brian arteriovenous malformation from the Neurosurgery, in Tiantan hopital of Capital Medical University during the period of 2009-2013,which were diagnosed by digital subtraction angiography(DSA) and confirmed by pathology after operation treatment. Through the injection of contrast agents in each DSA images and time interval of the taken to calculate each patient blood in the brain arteriovenous malformation arteriolar arterial(A) and venous(V) drainage time interval.Artery and vein appear down to zero at the same time, vein later than artery frame down to 1, so on. According to the state of hemodynamic the patients were devided into two groups: high blood flow dynamics model(A-V<2),20 cases;low blood flow dynamics model(A-V>2),20 cases.Stained the selected paraffin embedded tissue sections Respectively by immunohistochemical method.Regarded the expression of VEGF and DLL4 as positive result, and observed the result under optical microscope. The staining results were divided into two groups, strong positive and weak positive, then the data were analyzed by SPSS.Results:The expression of DLL4 is in vascular endothelial cells,in 40 patients,there are 14 cases in strong positive group and 26 cases in weak positive group. The expression of VEGF is in the cytoplasm of vascular endothelial cells and the surrounding:there are 26 cases in strong positive group and 14 cases in weak positive group.Combined with the state of hemodynamic, they can be divided into four groups: high blood flow dynamics model of VEGF,strong positive group 15 cases;weak positive group 5 cases low blood flow dynamics model of VEGF,strong positive group 11 cases;weak positive group 9 cases.High blood flow dynamics model of DLL4,strong positive group 3 cases;weak positive group 17 cases.Low blood flow dynamics model of DLL4,strong positive group 11 cases;weak positive group 9 cases. Conducted correlation analysis by SPSS16.0:DLL4 group,P=0.008<0.05,there is significant difference in statistical analysis, VEGF group,P=0.185>0.05 there is no significant difference in statistical analysis. It is suggested that the expression level of DLL4 is related to the the hemodynamic of brian arteriovenous malformation vascular mass,and the Pearson correlation coefficient C is 0.4. But the the expression level of VEGF is not related to the the hemodynamic of brian arteriovenous malformation vascular mass. Compared the expression level of VEGF and DLL4,there is significant difference in statistical analysis, P=0.007<0.05. It is found different that the expression level of VEGF and DLL4 in brian arteriovenous malformation vascular mass.Concusion:In recent years, it is found that Notch signal pathway and vascular endothelial growth factor(VEGF) interact, and regulate the process of angiogenesis in common. A recent study of tumor angiogenesis mechanism shows that DLL4-Notch signaling pathway plays an important role in it. The high expression of DLL4 inhibits the tumor angiogenesis, when the low expression of it increases the tumor angiogenesis. As the tumor vessel is no function, it reduces the rate of tumor growth. And a number of studies indicate that DLL4 is the downstream regulated gene of VEGF.By the up regulation of VEGFR-1 receptors and the down regulation of VEGFR-2 receptor, It inhibits the VEGF expression in reverse, to weaken the role of VEGF to promote the angiogenesis, to reduce the angiogenesis.At present, the digital subtraction angiography(DSA) is currently recognized as the gold standard in clinic for diagnosing brian arteriovenous malformation vascular mass.It can make a definite diagnosis of the size, shape, artery origin of arteriovenous malformation vascular mass, of the venous drainage direction and the dilatation. According to the partition interval(A-V),which comes from the blood through artery to vein,that express the state of hemodynamics.The smaller the interval is, the greater the hemodynamics is.Due to the recent application of ultrasound in brian arteriovenous malformation excision, we detect the resistance index(RI) to present the hemodynamic status of abnormal vascular mass. The smaller RI value is, the high hemodynamics is. The recent epidemiological survey of Tiantan hospital discovers the RI value of arteriovenous malformation vascular mass is less than that of the normal brian vessels, which indicates that the hemodynamic status of abnormal vascular is higher than that of the normal group and in the hyperdynamic state for a long time.The experimental results confirms that there is relevance between the expression of DLL4 and the hemodynamics of brian arteriovenous malformation vascular mass,and they interacts to between common abnormal regulation of vascular mass. Can inhibit the proliferation of vascular endothelial cells with high expression of DLL4 under the condition of low blood flow dynamics, reduce angiogenesis; whereas high hemodynamic state with low DLL4 expression increased angiogenesis and collateral anastomoses promotes brian arteriovenous malformation vascular mass of abnormal development. The experiment also indicated that DLL4 and VEGF exist difference in the expression of abnormal vascular mass on vascular endothelial cells. Further research on the interaction mechanism between DLL4 and hemodynamics, the mechanism of interaction between and DLL4-Notch signaling pathway and VEGF, can provide theoretical foundation and experimental basis for the clinical formed by changing the hemodynamic status and improve the clinical symptoms and arteriovenous malformation vascular mass anomaly.