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

Area of Science:

• Cardiovascular Biology
• Genetics
• Molecular Medicine

Background:

• Thoracic aortic aneurysm and dissection (TAAD) are severe complications of Loeys-Dietz syndrome, often linked to TGFB2 mutations.
• The specific role of vascular smooth muscle cell (SMC)-derived TGFβ2 in postnatal aortic health and disease progression was previously unclear.

Purpose of the Study:

• To investigate the function of vascular SMC-specific TGFβ2 in maintaining aortic wall homeostasis and preventing TAAD.
• To establish a genetic mouse model for studying TGFB2-associated aortopathy.

Main Methods:

• Generated tamoxifen-inducible, SMC-specific Tgfb2 conditional knockout (cKO) mice.
• Induced Tgfb2 deletion in adult mice and analyzed aortic pathology, SMC behavior, extracellular matrix composition, and signaling pathways.
• Utilized lineage tracing and molecular profiling techniques.

Main Results:

• SMC-specific Tgfb2 deletion induced rapid, progressive aneurysms, dissections, and rupture in the thoracic aorta.
• Loss of Tgfb2 led to SMC de-differentiation, elastic fiber fragmentation, medial degeneration, and altered ECM deposition (collagen, proteoglycans).
• Observed suppressed canonical SMAD2/3 signaling and activated non-canonical MAPK pathways (p38, pERK1/2).

Conclusions:

• Vascular SMC-derived TGFβ2 is essential for postnatal aortic homeostasis, regulating SMC differentiation and ECM integrity.
• Disruption of SMC-specific Tgfb2 signaling precipitates TAAD, offering mechanistic insights into TGFB2-associated aortopathy.
• The developed mouse model is valuable for evaluating targeted therapies for TAAD.