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Departments of 1 Medicine and 2 Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
We examined the effect of hypoxia and high glucose (HG) on ANG II type 1 (AT1) receptor expression and proliferation in cultured vascular smooth muscle (VSM) cells. Exposure of quiescent cells to hypoxia in a serum-free DME-Ham's F-12 medium for 6-24 h induced a progressive increase in AT1 mRNA expression. Exposure of cells to 24 h of hypoxia also resulted in a significant increase in ANG II receptor binding as assessed with 125I-labeled ANG II. Treatment with ANG II (1 µM) for 24 h under normoxic conditions caused an ~1.5-fold increase in both DNA synthesis and cell number, which was enhanced to ~3.0-fold under hypoxic conditions. An AT1 receptor antagonist (losartan, 10 µM) blocked the ANG II-induced increase in DNA synthesis under both normoxic and hypoxic conditions. Incubations in HG medium (25 mM) for 12-24 h under normoxic conditions induced an ~2.5-fold increase in AT1 mRNA levels, which was markedly enhanced by hypoxia to ~5.5-fold at 12 h and ~8.5-fold at 24 h. ANG II under HG-normoxic conditions caused a complete downregulation 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 the development of atherosclerosis in diabetes.
vascular smooth muscle cells; diabetes; chronic hypoxia; cell growth; angiotensin II receptor
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