Smad4 Deficiency in Smooth Muscle Cells Initiates the Formation of Aortic Aneurysm
Rationale: Aortic aneurysm is a life-threatening cardiovascular disorder due to 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 (MMP12), which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of MMP12 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.
- Received November 19, 2015.
- Revision received December 12, 2015.
- Accepted December 21, 2015.