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bioRxiv · 10.1101/2025.10.01.679917

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

Azhar, M.·Gebere, M. G.·Chakrabarti, M.·Azhar, A.·Wang, X.·Vyavahare, N. R.·Johnson, J.
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Abstract

ObjectiveThoracic 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 TGF{beta}2 in postnatal aortic homeostasis and disease remains undefined. Approach and ResultsWe 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 TGF{beta} signaling via p38 and pERK1/2 MAPK pathways. ConclusionsThese findings demonstrate that TGF{beta}2 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 TGF{beta} 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. HighlightsO_LIPostnatal, SMC-specific Tgfb2 deletion in mice caused rapidly progressive thoracic aortic aneurysms, dissections, and fatal rupture. C_LIO_LILoss of Tgfb2 disrupts SMC contractile phenotype and ECM homeostasis, leading to medial degeneration, elastin fragmentation, and abnormal collagen/proteoglycan accumulation. C_LIO_LICanonical TGF{beta}-SMAD signaling is suppressed, while MAPK pathways are activated, indicating ligand-specific signaling imbalance. C_LIO_LIFindings highlight TGF{beta}2 as a central regulator of postnatal aortic homeostasis and suggest that targeted ligand-specific therapeutic strategies may better preserve aortic wall stability. C_LI SignificanceThis study identifies smooth muscle cell-derived TGF{beta}2 as a critical, nonredundant regulator of postnatal aortic wall integrity, linking its loss to thoracic aortic aneurysm, dissection, and rupture, and highlighting TGF{beta}2 ligand-specific signaling as a targeted therapeutic target. Graphical AbstractSmooth muscle cell-derived TGF{beta}2 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 TGF{beta}2 as a nonredundant, ligand-specific regulator and potential therapeutic target in thoracic aortopathy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/679917v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1ef41d3org.highwire.dtl.DTLVardef@ca8feborg.highwire.dtl.DTLVardef@aebce4org.highwire.dtl.DTLVardef@1f3599b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Azhar, M., Gebere, M. G., Chakrabarti, M., Azhar, A., Wang, X., Vyavahare, N. R., Johnson, J.. 2025-10-03. Smooth Muscle Cell-Specific TGFβ2 Protects Against Thoracic Aortic Aneurysm and Dissection in Mice. https://doi.org/10.1101/2025.10.01.679917

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