Marfan syndrome results from fibrillin-1 (FBN1) mutations. Beyond weakening connective tissue scaffolding, which additional molecular mechanism links fibrillin-1 deficiency to aortic aneurysm formation?

• A FBN1 mutations reduce collagen cross-linking activity of LOX enzyme, directly causing type I collagen fragility in aortic media
• B FBN1 mutations cause constitutive activation of mTORC1 in aortic SMCs, driving autophagy failure and intracellular elastin accumulation that causes medial degeneration
• C Fibrillin-1 normally stabilizes heparan sulfate proteoglycans that prevent elastase activity; FBN1 loss allows unregulated matrix elastase activity independent of TGF-β
• D Fibrillin-1 normally sequesters latent TGF-β in the extracellular matrix; loss of fibrillin-1 releases excess active TGF-β1/3, which drives aortic smooth muscle cell apoptosis, matrix metalloproteinase upregulation, and elastin loss via SMAD2/3 and ERK signaling — losartan (ARB) reduces TGF-β signaling and slows aortic root dilation in Marfan mouse models ✓

Explanation

Fibrillin-1 is a glycoprotein that forms microfibrils, providing structural support to elastic fibers. Beyond this structural role, fibrillin-1 contains multiple TGF-β-binding domains that sequester latent TGF-β (within LTBP-fibrillin complexes) in the extracellular matrix. FBN1 mutations impair this sequestration, leading to excess release and activation of TGF-β1 and TGF-β3. Overactive TGF-β-SMAD2/3 and TGF-β-ERK signaling causes aortic SMC apoptosis, MMP-2/9 upregulation, elastin fragmentation, and medial cystic degeneration. This explains why losartan (which blocks AT1R-dependent TGF-β induction) and TGF-β neutralization attenuate aortic aneurysm in fibrillin-deficient mice, providing a therapeutic rationale beyond mechanical structural repair.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.