Endothelial nitric oxide synthase gene transfer restores endothelium–dependent relaxations and attenuates lesion formation in carotid arteries in apolipoprotein E–deficient mice

Abstract

Nitric oxide (NO) and monocyte chemoattractant protein-1 (MCP-1) exert partly opposing effects in vascular biology. NO plays pleiotropic vasoprotective roles including vasodilation and inhibition of platelet aggregation, smooth muscle cell proliferation, and endothelial monocyte adhesion, the last effect being mediated by MCP-1 downregulation. Early stages of arteriosclerosis are associated with reduced NO bioactivity and enhanced MCP-1 expression. We have evaluated adenovirus-mediated gene transfer of human endothelial NO synthase (eNOS) and of a N-terminal deletion (8ND) mutant of the MCP-1 gene that acts as a MCP-1 inhibitor in arteriosclerosis-prone, apolipoprotein E-deficient (ApoE(-/-)) mice. Endothelium-dependent relaxations were impaired in carotid arteries instilled with a noncoding adenoviral vector but were restored by eNOS gene transfer (p < 0.01). A perivascular collar was placed around the common carotid artery to accelerate lesion formation. eNOS gene transfer reduced lesion surface areas, intima/media ratios, and macrophage contents in the media at 5-week follow-up (p < 0.05). In contrast, 8ND-MCP-1 gene transfer did not prevent lesion formation. In conclusion, eNOS gene transfer restores endothelium-dependent vasodilation and inhibits lesion formation in ApoE(-/-) mouse carotids. Further studies are needed to assess whether vasoprotection is maintained at later disease stages and to evaluate the long-term efficacy of eNOS gene therapy for primary arteriosclerosis.

Overexpression of microRNA‐138 alleviates human coronary artery endothelial cell injury and inflammatory response by inhibiting the PI3K/Akt/eNOS pathway

“…NO is a bifunctional endothelial vasodilator that suppresses platelet aggregation, leucocyte adhesion and proliferation of vascular smooth muscle cells. However, excessive NO can react with superoxide anions and produce strong oxidizing peroxynitrite anions (ONOO‐), which can further result in lipid peroxidation and direct damage to endothelial cells . As shown in this study, compared with the blank group, PI3K, Akt and eNOS mRNA levels were up‐regulated in the miR‐138 inhibitor group but were down‐regulated in the miR‐138 mimic and LY294002 groups.…”

Mcp-1, eNOS, tPA and PAI-1 Gene Polymorphism and Correlation of Genotypes and Phenotypes in Hepatopulmonary Syndrome

“…NO and MCP-1 exert partly opposing effects in vascular biology. NO plays a pleiotropic vasoprotective role including vasodilatation and inhibition of platelet aggregation, smooth muscle cell proliferation and endothelial monocyte adhesion, the last effect being mediated by MCP-1 down regulation [31]. In our study, polymorphic alleles of eNOS and MCP1 genes were shown to have different alterations in cirrhotic patients compared with controls.…”

Endothelial Dysfunction in the Apolipoprotein E-deficient Mouse: insights into the influence of diet, gender and aging

“…Similarly, aortas from young apoE -/- mice fed a regular chow diet exhibit normal eNOS expression and normal dilation responses to ACh [63,64]. However, transfer of the eNOS gene into apoE -/- mice carotid arteries in vivo results in increased eNOS expression levels and normalized relaxation responses to ACh [72]. Interestingly, apoE -/- mice fed a Western-type diet exhibit increased vascular ET-1 production, reduced endothelial NO release, and impaired endothelium-dependent relaxation, which are all normalized by chronic blockage of the ET A receptor [68].…”