Nifedipine Indirectly Upregulates Superoxide Dismutase Expression in Endothelial Cells via Vascular Smooth Muscle Cell–Dependent Pathways

Abstract

Background-Calcium antagonists normalize endothelial dysfunction in many cardiovascular diseases. There is no known receptor, however, for calcium antagonists in endothelial cells (ECs). We hypothesized that vascular smooth muscle cells (VSMCs) are involved in the mechanism underlying the normalization of endothelial dysfunction by calcium antagonists. Methods and Results-Coculture studies with ECs and VSMCs were performed to determine whether VSMCs mediate modulation of endothelial superoxide dismutase (SOD) activity and expression induced by the calcium antagonist nifedipine. Nifedipine induced upregulation of SOD activity in rat aortic segments but had no effect on SOD expression or activity in ECs or VSMCs cultured individually. When ECs were cocultured with VSMCs, however, nifedipine upregulated SOD expression and activity in ECs. Nifedipine stimulated vascular endothelial growth factor (VEGF) production from VSMCs, and this stimulation of VEGF production was abolished by HOE-140, an antagonist of the bradykinin B 2 receptor. A neutralizing antibody against VEGF inhibited the upregulation of endothelial SOD by nifedipine. In addition, recombinant VEGF induced an increase in the levels of SOD expression in ECs, and supernatant derived from nifedipine-treated VSMCs enhanced NO production from ECs. This increase in NO production by the supernatant was inhibited by preincubation of ECs with SOD antisense oligodeoxyribonucleotides. Conclusions-The

Influence of nifedipine coat-core and amlodipine on systemic arterial stiffness modulated by sympathetic and parasympathetic activity in hypertensive patients

“…Secondly, our study demonstrated that NIF treatment significantly reduced the levels of hs-CRP and vWF compared with AML, and it suggested that NIF treatment may improve the vascular endothelial function. These findings are supported by reports that NIF has stronger anti-inflammatory activity 39 and stronger anti-atherosclerotic effects including an antioxidant action 40,41 than other CCBs. Recently, the ENCORE study from Europe 42 demonstrated that long-acting nifedipine GITS improves acetylcholine sensitivity in patients with coronary artery disease, suggesting that NIF treatment could also improve vascular endothelial function.…”

Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling

“…This result is also supported by our previous finding that nifedipine indirectly enhances NO production by endothelial cells by stimulating vascular endothelial growth factor release from the VSMCs. 23 Our present findings have the important implication that regeneration of endothelial cells and upregulation of endothelial NO synthase expression via Akt signaling activated by vascular endothelial growth factor and other growth factors may not be suppressed by calcium antagonists. 24,25 The number of functional L-type calcium channels significantly decreased in dedifferentiated VSMCs and increased on differentiation.…”

Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat

“…Thus, our findings on plasma nitrate and nitrite concentrations and on superoxide anion generation are consistent with the interpretation that the availability of NO is inversely correlated with the magnitude of superoxide anion generation. VEGF has been reported to upregulate the expression of superoxide dismutase, a major superoxide scavenger, in endothelial cells [7]. Moreover, reductions in superoxide dismutase have been reported to inhibit endothelium-dependant relaxation through the inactivation of NO [4].…”

“…Treatments that preserve vascular function would therefore be of obvious therapeutic benefit. Vascular endothelial growth factor (VEGF) is a potential candidate as it has been reported to upregulate superoxide dismutase in isolated endothelial cells [7]. In view of the altered acetylcholine-evoked vascular responses typically seen in the diabetic state [3,8], we sought to determine whether chronic treatment with VEGF early in the disease can preserve 'normal' acetylcholine-evoked responses in these rats, despite their uncontrolled diabetes.…”