TY - JOUR
T1 - Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-beta Signaling
AU - van der Pluijm, Ingrid
AU - Vliet, Margreethe
AU - von der Thüsen, Jan
AU - Robertus, Jan - Lukas
AU - Ridwan, Yanto
AU - Heijningen, Paula
AU - Thiel, Bibi
AU - Vermeij, Marcel
AU - Hoeks, Sanne
AU - Offerman, Luna
AU - Verhagen, Hence
AU - Kanaar, Roland
AU - Bertoli Avella, AM
AU - Essers, J.
PY - 2016
Y1 - 2016
N2 - Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-beta-activated transcription. Although TGF-beta-related gene mutations result in aneurysms, the underlying mechanismis unknown. Here, we examined aneurysm formation and progression in Smad3(-/-) animals. Smad3(-/-) animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3(-/-) aortas showed increased nuclear pSmad2 and pErk, indicating TGF-beta receptor activation, downstream TGF-beta-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3(-/-) aortas implied that aortic damage and TGF-beta receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-beta activated transcription resulted in increased Smad3(-/-) VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-beta signaling, immune suppression may be more beneficial. (C) 2016 The Authors. Published by Elsevier B.V.
AB - Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-beta-activated transcription. Although TGF-beta-related gene mutations result in aneurysms, the underlying mechanismis unknown. Here, we examined aneurysm formation and progression in Smad3(-/-) animals. Smad3(-/-) animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3(-/-) aortas showed increased nuclear pSmad2 and pErk, indicating TGF-beta receptor activation, downstream TGF-beta-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3(-/-) aortas implied that aortic damage and TGF-beta receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-beta activated transcription resulted in increased Smad3(-/-) VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-beta signaling, immune suppression may be more beneficial. (C) 2016 The Authors. Published by Elsevier B.V.
U2 - 10.1016/j.ebiom.2016.09.006
DO - 10.1016/j.ebiom.2016.09.006
M3 - Article
C2 - 27688095
SN - 2352-3964
VL - 12
SP - 280
EP - 294
JO - EBioMedicine
JF - EBioMedicine
ER -