We examined the effect of hypoxia and high glucose (HG) on Ang II type I (AT1) receptor expression and proliferation in cultured vascular smooth muscle (VSM) cells. Quiescent cells exposed to hypoxia in a serum-free DME/F12 medium for 6-24 hours induced a progressive increase in AT1 mRNA expression. Cells exposed to 24 hours of hypoxia also resulted in a significant increase in Ang II receptor binding as assessed with 125 I-labeled Ang II. Treatment with Ang II (1 µmol/l) for 24 hours under normoxic conditions caused ~ 1.5 fold increase in both DNA synthesis and cell number, which were enhanced to ~ 3.0 fold under hypoxic conditions. An AT1 receptor antagonist (losartan, 10 µmol/l) blocked the Ang II-induced increase in DNA synthesis under both normoxic and hypoxic conditions. Incubations in HG medium (25 mmol/l) for 12-24 hours under normoxic conditions induced ~ 2.5 fold increase in AT1 mRNA levels, which was markedly enhanced by hypoxia to ~ 5.5 fold at 12 hours and ~ 8.5 fold at 24 hours, respectively. Ang II under HG-normoxic conditions caused a complete down-regulation of AT1 expression, which was prevented by hypoxia. These results demonstrate an upregulation of AT1 receptor expression by hypoxia and HG in cultured VSM cells, and suggest a mechanism for enhanced Ang II-induced VSM cell proliferation and to the development of atherosclerosis in diabetes. 2 H-00625-2002R
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