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 (Tgfb2cKO) by crossing Tgfb2flox alleles with Myh11CreERT2 and ROSAmT/mG lineage reporter mice. Tgfb2 deletion was induced at 4 weeks of age. Tgfb2cKO 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 TGFβ2 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 TGFβ2 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.
Azhar et al. (Fri,) studied this question.