| Background:Sublingual collateral vessels diagnosis is an important component of traditional tongue diagnosis. Because it is easy to check and reflects fast, it is also an important indications of human qi-blood, fluid-humor and static blood in clinical diagnosis. With long time clinical observation of primary liver cancer and cirrhosis, it is found that a large percent of those patients are suffering sublingual collateral vessels expansion, morphology circle change and the color change to blue, purple and crimson. These changes are sensitive and significantly related to the progress of treatment and the prognosis of the patience.In Traditional Chinese Medicine, liver and tongue are deep related. Lingshu·meridian vessel is recorded:"Jueyin is liver meridian, and the liver meridian contacts the root of the tongue", liver abnormalities may reflect on the tongues with corresponding changes. Current researches suggest that abnormal formation of sublingual collateral vessels of these patients may be related to the increased stress of portal vein. For example, Shiying Jin directs that sublingual collateral vessels abnormalities may be associated with increased venous pressure which is caused by portal hypertension through animal experiments. Meanwhile, the result that the pathological changes of sublingual collateral vessels and determined the stress of portal vein of 118 portal hypertension patients at surgery also confirm that sublingual collateral vessels varicose rate is 100% in the portal hypertension patients. The results of staggered research also show that sublingual collateral vessels abnormalities in primary liver cancer patients are directly related to some indicators of portal vessels and local hemodynamic. However, the relation between portal hypertension and abnormal formation of sublingual collateral vessels is still unknown; especially the molecular mechanism of sublingual collateral vessels abnormality keeps blank in the current portal hypertension. As the parts of human venous vascular system, it is believed that the sublingual collateral vessels and hepatic portal vein are related with each other in pathology. At the same time, it is noted that abnormal sublingual collateral vessels expression does not only appear on color, shape and other abnormalities in the process of liver cancer and cirrhosis, but also blood stasis points around sublingual collateral vessels and the increasing number of small collateral vessels with blood stasis. Therefore, it is difficult to fully explain just with the increasing portal vein pressure which causes sublingual collateral vessels passive expansion. This suggests us that abnormal sublingual collateral vessels which are caused by liver cirrhosis portal hypertension have deeper material basis.With the developing research of modern cancer and molecular biology, molecular mechanism of angiogenesis has been gradually revealed. For the adults, physiological and pathological mechanisms of angiogenesis are the main blood vessel formation. Lots of elements are playing positive regulatory roles in angiogenesis. In factors that known in angiogenesis, the vascular endothelial growth factor (Vascular Endothelial Growth Factor, VEGF) are the most important. Hypoxic response, mechanical stress and a variety of mechanisms are involved in the VEGF gene induction. In hypoxia circumstances, the hypoxia-inducible factor-1 (HIF-1) increase the expression of VEGF protein by stimulating VEGF transcription and enhancing stability of VEGF mRNA. VEGF through endothelial nitric oxide syntheses to stimulating the synthesis of nitric oxide mediated vascular dilatation and increase its permeability. In recent years research has been confirmed that the lungs and spleen also exists angiogenesis in the process of portal hypertension. It is directed that morphological diversity, disturbance and disorder of abnormal sublingual collateral vessels are similar with different subtypes of VEGF-induced angiogenesis. Therefore, envisaging under the "angiogenesis" theory, pay the focus on the perspective of angiogenesis to explore the possible molecular mechanism of abnormal sublingual collateral vessels in cirrhosis portal hypertension model.Objective:This research aim to observe its sublingual collateral vessels changes and explore the relationship between VEGF and abnormal sublingual collateral vessels from the perspective of angiogenesis by creating liver cirrhosis portal hypertension canine model, in order to provide data support for revealing the molecular mechanism of abnormal sublingual collateral vessels. Methods:Beagle dogs were randomly divided into normal group and model group. There were 6 dogs in each group. Canine model of cirrhosis portal hypertension was established by injecting dimethylnitrosamine (DMN) into portal vein once a week which would last for 7 weeks. The characteristics of sublingual collateral vessels were observed; portal venous pressure was measured by bioelectricity recording system; Nitric oxide in serum was detected by nitrate reductase method; The vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α(HIF-1α) expression of serum was detected by ELISA;VEGF and HIF-1αexpression of sublingual collateral vessels were detected by immunohistochemical. VEGF mRNA and HIF-1αmRNA expression level of sublingual collateral vessels was detected by Real-Time PCR.Results:The morphous and color of sublingual collateral vessels of the beagle dogs in model group changed obviously compared with those in normal control group. sublingual collateral vessels appear enlarged tortuous, the increased number of small collateral vessels and even bluish purple; NO in serum of the beagle dogs was significantly increased in model group; VEGF, HIF-1αprotein expression was significantly higher in serum; Immunohistochemical results showed that there is almost no expression of VEGF and HIF-1αof sublingual collateral vessels in the normal control group. But the expression of VEGF and HIF-1αprotein in cirrhotic portal hypertension group increased; VEGF mRNA, HIF-1αmRNA also significantly increased.Conclusion:Changes of portal pressure may lead to the formation of the abnormal sublingual collateral vessels. The sublingual vascular endothelial VEGF and HIF-la high expression may be involved in this process, which is one important molecular mechanism for abnormal sublingual collateral vessels... |
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