Abstract 1196: Vascular Endothelial Cells specific Endothelin-1 mediates Early Inflammation in Murine Model of Neointimal Formation
Complex mechanism of the chronic inflammatory process in vascular injury and atherosclerosis involves various types of cells and cytokines. Previous in vitro studies suggest that Endothelin-1 (ET-1) is produced by those cells, induces expression of several adhesion molecules and mediates the leukocyte-endothelial interaction. In the present study, we sought to determine whether local endothelial ET-1 plays a direct effect on early inflammation and neointimal formation as a response to vascular injury in vivo. Using Cre-loxP system and Tie-2 Cre promoter, Vascular Endothelial ET-1 Knockout (VEETKO) mice was generated. The mice showed 60% reduction of ET-1 mRNA level at major organs and undetected serum ET-1 level. To induce vascular inflammation, complete ligation of the left common carotid artery was performed in 12-weeks-old male VEETKO (n=35) and Wild Type (WT) littermates (n=34). Inhibition of vascular endothelial ET-1 prevented the 4-fold increase in ET-1 mRNA level of carotid artery after ligation, in contrast to that of WT mice. This prevention resulted in lower vascular inflammation revealed by lower mRNA and protein level of PECAM-1, ICAM-1, and MCP-1 in VEETKO mice. The lack of ET-1 in endothelium further inhibited the adhesion of inflammatory cells at early days after ligation as compared to that adhered in endothelium of WT mice (cell numbers, 20.7±4.9 vs. 54.6±3.9 respectively, p<0.05, VEEETKO n=8/WT n=10). Observation at 4 weeks after ligation noted lower neointimal formation in VEETKO mice (n=11) as compared to WT littermates (n=12) (neointimal/medial ratio, 0.2±0.03 vs. 0.8±0.25 respectively, p<0.05). Changes in carotid flow gave no hemodynamical effect as sistolic blood pressure maintained significantly lower in VEETKO mice as compared to WT mice (105.7±1.4 vs. 115.9±1.6 mmHg before ligation, p<0.05 and 105.7±2.4 vs.119.08±1.08 mmHg after ligation, p<0.05 n=20 each). In conclusion, these data demonstrated that lack of vascular endothelial ET-1 reduced inflammatory response of the vascular wall followed by inhibition of neointimal formation confirming the role of local endothelial ET-1 in mediating inflammation in vascular injury, in addition to its potent vasoconstrictor and proliferating effect.