Unraveling the role of TGFβ signaling in thoracic aortic aneurysm and dissection using Fbn1 mutant mouse models

• Published in: Matrix biology Vol. 123; pp. 17 - 33
• Main Authors: Deleeuw, Violette, Carlson, Eric, Renard, Marjolijn, Zientek, Keith D., Wilmarth, Phillip A., Reddy, Ashok P., Manalo, Elise C., Tufa, Sara F., Keene, Douglas R., Olbinado, Margie, Stampanoni, Marco, Kanki, Sachiko, Yanagisawa, Hiromi, Mosquera, Laura Muiño, Sips, Patrick, De Backer, Julie, Sakai, Lynn Y.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2023
• Subjects: Aortic aneurysm and dissection; Fibrillin; Marfan syndrome; Mouse models; TGFβ signaling; Aortic aneurysm and dissection; Fibrillin; Mouse models; TGFβ signaling; Marfan syndrome
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2023.09.001

•Reducing the expression of Tgfb2 or replacing wildtype Fbn1 with a mutant allele in which the first hybrid domain is deleted showed comparable deleterious effects on aortic disease severity in Fbn1 mutant mice modeling Marfan syndrome.•Reduced TGFβ signaling and increased amounts of mast cell proteases were associated with aortic “microdissections” in mice in which the first hybrid domain is deleted in fibrillin-1.•Increased quantities of extracellular matrix proteins were identified in Fbn1 mutant mice with aortic aneurysm (without rupture).•Marked reductions in quantities of fibrillins and microfibril proteins were revealed in Fbn1 mutant mice with aortic aneurysm and rupture.•Context-dependent effects on TGFβ signaling were associated with Fbn1 mutant mice representing mild to severe thoracic aortic disease. Although abnormal TGFβ signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, its precise role in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to elucidate the role of TGFβ signaling in three Fbn1 mutant mouse models representing a range of aortic disease from microdissection (without aneurysm) to aneurysm (without rupture) to aneurysm and rupture. Results indicated that reduced TGFβ signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGFβ signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGFβ signaling, were associated with aortic rupture. Our data indicate that TGFβ signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.