Abstract
BackgroundThe aim of the current study was to investigate the role of p55 TNF Receptor (p55 TNFR), the main signaling receptor for the pro-inflammatory cytokine tumor necrosis factor (TNF), in the development of two vascular disorders: atherosclerosis and angiotensin (Ang) II-induced abdominal aortic aneurysms (AAA).Methodology/Principal Findingsp55 TNFR deficient mice were crossed to an LDL receptor deficient background and were induced for the development of either atherosclerosis or AngII-induced AAA, and compared to littermate controls, wild-type for p55 TNFR expression. p55 TNFR deficient mice developed 43% smaller atherosclerotic lesions in the aortic sinuses compared to controls. Moreover, expression of CD68, a macrophage specific marker, exhibited a 50% reduction in the aortic arches. Decreased atherosclerosis correlated with a strong down-regulation in the expression of adhesion molecules, such as VCAM-1 and ICAM-1, by p55 TNFR deficient endothelium. In addition, expression levels of the pro-inflammatory cytokines and chemokines TNF, IL-6, MCP-1 and RANTES were significantly reduced in aortas of p55 TNFR deficient mice. In contrast, in the AngII-induced model of AAA, p55 TNFR deficiency correlated with a slight trend towards increased aneurismal lethality, but the incidence of aortic rupture due to a dissecting aneurysm, and the expansion of the suprarenal aorta were not significantly different compared to controls.Conclusion/SignificanceWe found that p55 TNFR expression promotes atherosclerosis, among other mechanisms, by enhancing expression of endothelial adhesion molecules, while it seems to have no major role in the development of AngII-induced AAA.
Highlights
Vascular inflammatory processes, characterized by the accumulation in the arterial wall of immune cells like monocytes/ macrophages and lymphocytes, are crucial events in the pathogenesis of major vascular diseases such as atherosclerosis and abdominal aortic aneurysms (AAA) [1,2]
Conclusion/Significance: We found that p55 TNFR expression promotes atherosclerosis, among other mechanisms, by enhancing expression of endothelial adhesion molecules, while it seems to have no major role in the development of AngIIinduced AAA
Regarding the cell-type specific role of this receptor, we have recently shown that bone-marrow derived p55 TNFR promotes atherosclerosis development by enhancing lesional foam-cell formation and by promoting the expression of pro-atherosclerotic chemokines, like MCP-1 [10]
Summary
Vascular inflammatory processes, characterized by the accumulation in the arterial wall of immune cells like monocytes/ macrophages and lymphocytes, are crucial events in the pathogenesis of major vascular diseases such as atherosclerosis and abdominal aortic aneurysms (AAA) [1,2]. As indicated by the authors, this study presented some limitations since it appeared that there was a slight alloimmune reaction accelerating atherosclerosis, possibly elicited by ApoE secreted by graft smooth muscle cells. This might complicate the elucidation of the actual role of vascular wall p55. The aim of the current study was to investigate the role of p55 TNF Receptor (p55 TNFR), the main signaling receptor for the pro-inflammatory cytokine tumor necrosis factor (TNF), in the development of two vascular disorders: atherosclerosis and angiotensin (Ang) II-induced abdominal aortic aneurysms (AAA)
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