Smad4 Deficiency in Smooth Muscle Cells Initiates the Formation of Aortic Aneurysm

Abstract

Rationale: Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-β (TGF-β) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-β signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown. Objective: To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms. Methods and Results: Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-β receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-β in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs. Conclusions: The findings reveal that Smad4-dependent TGF-β signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-β signaling loss-of-function mutations.

Identifying suitable reference genes for gene expression analysis in developing skeletal muscle in pigs

“…Many studies investigated the mechanism of skeletal muscle development by performing gene expression analysis (Krist et al, 2015; Wang, Xiao & Wang, 2016; Zhang et al, 2016a; Zhang et al, 2015). However, it is crucial to select accurate reference genes to normalize target gene expression levels during skeletal muscle development in mammals.…”

“…Studies of muscle development often explore gene expression under different conditions (Krist et al, 2015; Wang, Xiao & Wang, 2016; Zhang et al, 2016a; Zhang et al, 2015). The expressions of most genes display variable expression levels in prenatal and postnatal periods, and reference genes that are frequently used for other experiments are not suitable for studies of skeletal muscle development.…”

A Functional Variant of SMAD4 Enhances Thoracic Aortic Aneurysm and Dissection Risk through Promoting Smooth Muscle Cell Apoptosis and Proteoglycan Degradation

“…SMAD4 plays a pivotal role in the pathological progression of vascular disorder (Zhang et al, 2016). SMAD4 , a member of Smad family, is a central mediator in the canonical TGF-β signaling.…”

“…It regulates biological processes important for the pathogenesis of TAAD, such as SMCs migration and proliferation, extracellular matrix degradation (Mao et al, 2012). SMAD4 -deficient SMCs can trigger aortic wall inflammation by producing chemokines and recruiting macrophages (Zhang et al, 2016). Besides, SMAD4 also play essential roles in cardiogenesis, blood vessel remodeling, maturation and integrity (Jiao et al, 2003; Lan et al, 2007; Qi et al, 2007; Song et al, 2007).…”

Modern molecular genetic and biochemical predictors of genital prolapse (a review)

“…В то же время TGF-β 1 являет-ся стимулятором выработки коллагена, усиливая формирование межклеточного матрикса. Понижен-ная экспрессия TGF-β 1 , а также дефицит и/или функ-циональная неактивность его рецепторов TGFβR1 обусловливает сниженную экспрессию CTGF (фак-тора роста соединительной ткани), что приводит к за-медлению роста и дифференцировки фибробластов и пониженному синтезу компонентов ЭЦМ [44,45]. Параллельно происходит активация матриксных ме-таллопротеиназ (MMPs) и ингибирование тканевых ингибиторов металлопротеиназ (TIMPs), что приво-дит к усилению фрагментации волокон ЭЦМ, усугу-бляет структурную реорганизацию соединительной ткани, снижает ее прочность и эластичность.…”