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Study on the Mechanism of Hypertension Caused by Sorafenib in Liver Cancer-Bearing Rats Based on VEGF Signal Pathway

Kaicheng Wang, People’S Hospital Of Huishan, Tingwang Jiang, The Affiliated Changshu Hospital Of Xuzhou Medical University

Abstract: To explore the mechanism of hypertension caused by sorafenib in liver cancer-bearing rats based on Vascular Endothelial-Growth Factor (VEGF) signal pathway. After the three groups (blank, liver cancer and Spontaneously Hypertensive Rat (SHR) groups, n = 30) were administered orally with sorafenib (2 mg/kg), the non-invasive tail arterial pressure measurement was employed to determine the changes in blood pressure (BP). Enzyme-linked immunosorbent assay measured the changes of VEGF and Nitric Oxide (NO) in serum. The expressions of Kinase insert Domain Receptor tyrosine kinase (KDR-CD), endothelial Nitric Oxide Synthase (eNOS), Bax and Bcl-2 were detected by Western blot. TUNEL assay detected the Apoptosis Index (AI) of cardiomyocyte. CD31 immunohistochemical staining was observed the changes of Myocardial Capillary Density (MCD). The BP and VEGF levels of the blank and SHR groups were not significantly (P > 0.05) different from those in the before treatment cohort, while the BP of the liver cancer group was significantly (P < 0.05) higher. VEGF level was significantly (P < 0.05) lower than before. Compared with the blank group, the levels of NO, KDR-CD, eNOS, Bcl-2/Bax and MCD in the liver cancer group were significantly (P < 0.05) lower than those in the after administration, while the myocardial cell AI increased significantly (P < 0.05). After antagonist intervention, the BPs and myocardial AI of the liver cancer and SHR groups were significantly lower than before the intervention. Besides, levels of KDR-CD, eNOS, Bcl-2/Bax protein, MCD, serum VEGF and NO were significantly higher than before the intervention (P<0.05). Induction mechanism of hypertension induced by sorafenib may be owing to the inhibition of the VEGF signaling pathway, and reduction of endothelial cells proliferation leading to blockade of NO synthesis. This causes vasoconstriction, while promoting myocardial cell apoptosis and decreasing capillary density, thereby inducing the occurrence of hypertension.
Keywords: apoptosis / blood pressure / liver cancer / Rat / VEGF signaling / VEGF Signal Pathway / Capillary Density

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