Smooth Muscle Cell-Specific TGFβ2 Protects Against Thoracic Aortic Aneurysm and Dissection in Mice

Objective

Thoracic aortic aneurysm and dissection (TAAD) are major complications of Loeys- Dietz syndrome caused by heterozygous TGFB2 mutations. While Tgfb2 knockout mice die at birth and adult heterozygotes develop late, non-dissecting or non-rupturing aneurysms, the role of vascular smooth muscle cell (SMC)–derived TGFβ2 in postnatal aortic homeostasis and disease remains undefined.

Approach and Results

We generated tamoxifen-inducible, SMC-specific Tgfb2 conditional knockout mice ( Tgfb2 cKO) by crossing Tgfb2 ^flox alleles with Myh11CreER ^T2 and ROSA ^mT/mG lineage reporter mice. Tgfb2 deletion was induced at 4 weeks of age. Tgfb2 cKO mice developed rapidly progressive aneurysms involving both ascending and descending aortas, with intramural dissection and/or rupture at the proximal descending aorta. Lineage tracing confirmed loss of Tgfb2 -deficient SMCs during disease progression. Histological and morphometric analyses revealed elastic fiber fragmentation, SMC loss and de-differentiation, medial thickening, adventitial fibrosis, and accumulation of collagen and proteoglycans. Molecular profiling demonstrated reduced expression of SMC contractile genes ( Acta2, Myh11 ), increased fibrillar collagen ( Col1a1 ) expression, early suppression of SMAD2/3 phosphorylation and increased non-canonical TGFβ signaling via p38 and pERK1/2 MAPK pathways.

Conclusions

These findings demonstrate that TGFβ2 derived from vascular SMCs is essential for postnatal aortic wall homeostasis by preserving SMC differentiation, maintaining extracellular matrix integrity, and supporting and preserving a proper balance of both canonical and non-canonical TGFβ signaling. Loss of SMC-specific Tgfb2 precipitates medial degeneration, aneurysm formation, dissection, and rupture, providing direct mechanistic insight into TGFB2 -associated aortopathy and establishing a robust novel genetic mouse model for evaluating targeted therapies in TAAD.

Highlights

• Postnatal, SMC-specific Tgfb2 deletion in mice caused rapidly progressive thoracic aortic aneurysms, dissections, and fatal rupture.

• Loss of Tgfb2 disrupts SMC contractile phenotype and ECM homeostasis, leading to medial degeneration, elastin fragmentation, and abnormal collagen/proteoglycan accumulation.

• Canonical TGFβ–SMAD signaling is suppressed, while MAPK pathways are activated, indicating ligand-specific signaling imbalance.

• Findings highlight TGFβ2 as a central regulator of postnatal aortic homeostasis and suggest that targeted ligand-specific therapeutic strategies may better preserve aortic wall stability.

Significance

This study identifies smooth muscle cell–derived TGFβ2 as a critical, nonredundant regulator of postnatal aortic wall integrity, linking its loss to thoracic aortic aneurysm, dissection, and rupture, and highlighting TGFβ2 ligand-specific signaling as a targeted therapeutic target.

Graphical Abstract

Smooth muscle cell–derived TGFβ2 maintains postnatal aortic wall homeostasis by preserving contractile gene expression, elastin architecture, and balanced ECM remodeling. Conditional deletion of Tgfb2 in SMCs shifts signaling from canonical SMAD2/3 to MAPK pathways, leading to medial degeneration, progressive aneurysm, dissection, and rupture—highlighting TGFβ2 as a nonredundant, ligand-specific regulator and potential therapeutic target in thoracic aortopathy.