The Mechanism Of TGF-β-Smad3Signal On The Development And Progression Of Aneurysm

Part I Loss of Smad3function is involved in aortic aneurysm formation.The transforming growth factor-β (TGF-β) cytokine pathway is involved in aortic aneurysm formation. Heterozygous loss-of-function Smad3mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3had a vascular phenotype similar to that of AOS and induced progressive aneurysms. We also identified a missense mutation (c.985A>G) in a Chinese family of thoracic aortic aneurysms. Elucidate the mechanisms underlying this previously unrecognized vascular phenotype, we found a focal loss of medial SMCs along with periarteriolar fibrosis thickening in the wall. IHC and Western blot analysis showed up-regulation of p-Smadl/5, p-Smad2, p-ERK1/2and p-JNK1in the proximal ascending aorta from Smad3-/-mice at the later stage. So we believe that the up-regulated TGF-β in SMCs at the later stage might be a repairing mechanism of aorta in response the changes at the early stage.Part II GM-CSF contributes to aortic aneurysms resulting from SMAD3deficiency.We have demonstrated that aortic dilation in Smad3-/-mice is initiated in the aortic root.These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. To investigate the role of hematopoietic cells in aneurysm onset in Smad3-/-mice,We found bone marrow transplants from Smad3-/-mice induced aortitis and aortic root dilation in irradiated wild-type recipient mice. Transplantation of CD4+T cells from Smad3-/-mice also induced aortitis in Smad3+/+recipient mice, while depletion of CD4+T cells in Smad3-/-mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, in Smad3+/-mice IFN-y deficiency increased, while IL-17deficiency improved, disease severity. Cytokine secretion was measured using a cytokine quantibody array, and Smad3-/-CD4+T cells secreted more GM-CSF than Smad3+/+CD4+T cells, which induced CD11b+Gr-1+Ly-6Chi inflammatory monocyte accumulation in the aortic root. Administration of anti-GM-CSF monoclonal antibody (mAbs) to Smad3-/-mice resulted in significantly less inflammation and dilation in the aortic root. We also found intense inflammatory infiltration and GM-CSF expression is observed in aortas specimens of these patients Therefore, GM-CSF might be potentially involved in the development of AOS.