Marfan syndrome predisposes to aortic root dilation and dissection due to FBN1 (fibrillin-1) mutations. Beyond structural weakness, a key pathophysiological mechanism involves signaling dysregulation that can be targeted therapeutically:

• A Loss of fibrillin-1 decreases VEGF binding, impairing angiogenesis
• B Increased collagen cross-linking by LOX enzyme causes aortic stiffness
• C Elastin mutations cause impaired elastic fiber recoil and aneurysm formation
• D Deficient fibrillin-1 microfibrils fail to sequester TGF-β, resulting in excessive TGF-β signaling that causes smooth muscle cell apoptosis and matrix degradation in the aortic wall ✓

Explanation

Fibrillin-1 microfibrils in the extracellular matrix normally sequester latent TGF-β (as part of LTBP complexes), preventing its activation. In Marfan syndrome, deficient/dysfunctional fibrillin-1 fails to sequester TGF-β, leading to excessive active TGF-β signaling in aortic smooth muscle cells. This excess TGF-β activates SMAD and ERK/MAPK pathways, causing upregulation of matrix metalloproteinases (MMPs), smooth muscle cell apoptosis, elastic fiber fragmentation ('cystic medial degeneration'), and ultimately aneurysm formation. This insight is the basis for using losartan (AT1R blocker that reduces TGF-β signaling) in addition to beta-blockers in Marfan syndrome management.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.