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Biomechanical signalling in atherosclerosis
001 TETRAHYDROBIOPTERIN-DEPENDENT ENOS COUPLING MEDIATES ENDOTHELIAL REGENERATION AND ATTENUATES VEIN GRAFT ATHEROSCLEROSIS IN APOE-KO MICE
Z. A. Ali1, N. J. Alp1, Y. Hu2, Q. Xiao2, A. M. Akthar1, G. Douglas1, A. L. Tatham1, J. P. deBono1, D. R. Greaves1, Q. Xu2, K. M. Channon1.1Cardiovascular Medicine, University of Oxford; 2Cardiological Sciences, St Georges Hospital, UK
As a result of surgical trauma, ischaemia and exposure to arterial pressure the majority of endothelial cells in vein grafts undergo necrosis or apoptosis early after surgery. We hypothesised that eNOS coupling mediates endothelial regeneration after vein bypass grafting. To investigate this, transgenic mice with endothelial-targeted overexpression of the essential eNOS coupling cofactor BH4 crossed onto ApoE-KO background (GCH/ApoE-KO) or their ApoE-KO littermates underwent bypass grafting of donor caval vein to the carotid artery. Grafts were constructed in four groups, either as isogenic grafts or in a crossover design between genotypes, and harvested 28 days post surgery. As isogenic grafts, BH4 augmentation reduced total vessel wall area by 61% (p<0.001) compared to ApoE-KO controls. However, when donor veins from ApoE-KO mice were grafted into recipient GCH/ApoE-KO mice the reduction in lesion area was maintained (47%, p<0.001), indicating a host derived phenotype. Conversely, when GCH/ApoE-KO donor veins were grafted into recipient ApoE-KO mice there was no reduction in lesion area compared to ApoE-KO controls. In keeping with these findings, transgenic GCH mRNA and vascular BH4 levels in ApoE-KO veins grafted into GCH/ApoE-KO recipients reached similar levels to GCH/ApoE-KO veins grafted into GCH/ApoE-KO mice, indicating host derived endothelial repopulation. When grafts were constructed in GCH/ApoE-KO mice expressing an endothelial reporter gene for beta-galactosidase (LacZ) using veins from non-LacZ GCH/ApoE-KO mice, endothelial repopulation was accelerated by 30% (p<0.01) compared to ApoE-KO veins grafted into ApoE-KO/LacZ recipients. Availability of BH4 …