• 作者：I. van der Pluijm ; PhD^a ; ^b ; ^c ; N. van Vliet ; BSc^b ; J.H. von der Thusen ; PhD^d ; J.L. Robertus ; PhD^d ; Y. Ridwan ; BSc^b ; P.M. van Heijningen ; BSc^b ; ^c ; B.S. van Thiel ; MSc^a ; ^b ; ^e ; M. Vermeij ; BSc^b ; S.E. Hoeks ; PhD^f ; R.M.G.B. Buijs-Offerman ; PhD^c ; H.J.M. Verhagen ; MD ; PhD^a ; R. Kanaar ; PhD^b ; ^g ; A.M. Bertoli-Avella ; MD ; PhD^c ; ¹ ; J. Essers ; PhD^a ; ^b ; ^g ; ^{j.essers@erasmusmc.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AOS ; aneurysm-osteoarthritis syndrome ; CTGF ; connective tissue growth factor ; ECM ; extracellular matrix ; MFS ; Marfan's syndrome ; MMP ; matrix metalloproteases ; TGF-β ; transforming growth factor β ; VSMC ; vascular smooth muscle cell ; LDS ; Loeys-Dietz syndrome ; SMAD ; SMA/MAD homologous
• 刊名：EBioMedicine
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：12
• 期：Complete
• 页码：280-294
• 全文大小：2446 K

•

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.