Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling
| Autor: | J.L. Robertus, Aida M. Bertoli-Avella, S.E. Hoeks, R.M.G.B. Buijs-Offerman, P.M. van Heijningen, Jeroen Essers, B.S. van Thiel, M. Vermeij, Roland Kanaar, Hence J.M. Verhagen, Yanto Ridwan, J.H. von der Thusen, N. van Vliet, I. van der Pluijm |
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| Přispěvatelé: | Clinical Genetics, Molecular Genetics, Surgery, Pathology, Internal Medicine, Anesthesiology, Radiotherapy |
| Jazyk: | angličtina |
| Předmět: |
Male
0301 basic medicine lcsh:Medicine Smad2 Protein SMAD 030204 cardiovascular system & hematology Gene mutation Loeys–Dietz syndrome Vascular biology VSMC vascular smooth muscle cell Muscle Smooth Vascular Extracellular matrix Mice Aortic aneurysm 0302 clinical medicine Transforming Growth Factor beta Extracellular Signal-Regulated MAP Kinases TGF-β signaling pathway TGF-β transforming growth factor β Mice Knockout lcsh:R5-920 LDS Loeys-Dietz syndrome biology integumentary system General Medicine Anatomy Immunohistochemistry ECM extracellular matrix Aortic Aneurysm Molecular Imaging Cell biology Connective Tissue Echocardiography AOS aneurysm-osteoarthritis syndrome cardiovascular system Female medicine.symptom lcsh:Medicine (General) Research Paper Signal Transduction Transcriptional Activation Inflammation MMP matrix metalloproteases Models Biological General Biochemistry Genetics and Molecular Biology CTGF connective tissue growth factor Mouse model 03 medical and health sciences medicine Animals Smad3 Protein Mortality Cell Proliferation SMAD SMA/MAD homologous lcsh:R X-Ray Microtomography medicine.disease Aneurysm Matrix Metalloproteinases Elastin CTGF Disease Models Animal 030104 developmental biology biology.protein MFS Marfan's syndrome |
| Zdroj: | EBioMedicine EBioMedicine, 12, 280-294. Elsevier EBioMedicine, Vol 12, Iss C, Pp 280-294 (2016) |
| ISSN: | 2352-3964 |
| DOI: | 10.1016/j.ebiom.2016.09.006 |
| Popis: | 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-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is 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-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β 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-β signaling, immune suppression may be more beneficial. Highlights • Smad3 deficiency leads to aortic aneurysms and sudden death in Smad3 knockout mice. • Upstream TGF-β receptor signaling is activated, yet downstream TGF-β-activated transcription is impaired in Smad3-/- VSMCs • Improper TGF-β induced downstream gene activation in Smad3-/- VSMCs impairs ECM formation and weakens aortic structure Mutations in the Smad3 gene cause aortic aneurysms and joint disorders. Since aneurysm growth is highly unpredictable in Smad3 patients, early diagnosis is of vital importance. Here we identify the molecular basis for this unpredictable and acute aneurysm growth using Smad3 knockout mice. Dysregulation of the downstream TGFβ signaling pathway due to absence of Smad3 weakens the extracellular matrix of vascular smooth muscle cells and changes the aortic composition, thereby leading to the attraction of immune cells. These findings provide a rationale for the variable clinical outcome in Smad3 patients and open up new intervention possibilities. |
| Databáze: | OpenAIRE |
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