Decreased Angiotensin II Receptors Mediate Decreased Vascular Response in Hepatocellular Cancer

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Abstract
The authors' objective was to determine the origin of the diminished pressor responsiveness of angiotensin II infusion in hepatoma by evaluating angiotensin II receptor status in normal liver, hepatoma tumor, and cultured hepatocytes and H4IIE cells. Hepatocellular cancer is a highly vascular tumor, where the neovasculature is unique in that it arises only from the hepatic arterial circulation, whereas normal liver has both hepatic arterial and portal venous blood supply. The tumor neovasculature is also characterized by an abnormal vascular reactivity to vasoconstrictors, including the response to angiotensin II. The altered response of tumor vasculature to angiotensin II offers a potential therapeutic opportunity for modulation of tumor blood flow. However, the origin of the decreased vascular response is unknown. The authors evaluated the hepatic vascular response to angiotensin II infusion by determining hepatic arterial blood flow to normal liver and to tumor by means of radioactive microspheres. The angiotensin II receptor status in the normal liver, hepatoma tumor, and cultured hepatocytes and H4IIE cells was determined by radioligand binding analysis and in cryostat sections derived from normal liver and hepatoma tumor by means of in situ binding analysis with biotinylated angiotensin II. Angiotensin II infusion decreased the hepatic arterial flow to normal liver and increased hepatoma to liver flow ratio. The number of angiotensin II receptors in normal liver was significantly higher than that in hepatoma (239 ± 20 fmol/mg protein in normal liver vs. 162 ± 15 fmol/mg protein in hepatoma) without a change in the affinity (4.4 ± 0.8 nM in normal liver vs. 4.7 ± 1.2 nM in hepatoma). H4IIE cells and primary hepatocytes had low receptor density. In situ binding analysis revealed that angiotensin II receptors were mainly on the smooth muscle cells of the neovasculature. The data suggests that the diminished vascular response to angiotensin II hepatoma may relate a loss of angiotensin II receptor on tumor neovasculature.

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