Spatial Patterns of Transforming Growth Factor Beta Signaling in Mgr‐/‐ Mouse Model of Marfan Syndrome

Abstract

The balance between wall stress and structure of a blood vessel is crucial for its optimal function and is maintained by remodeling. Marfan patients, harboring mutations of fibrillin1 (FBN1) gene, exhibit aberrant vascular remodeling, formation of aortic aneurysms and dissections. This is associated with altered signaling through transforming growth factor beta (TGFβ) pathway. Non‐invasive imaging and computational modeling of blood flow predict complex pattern of wall stress in the ascending aorta and arch. We hypothesized that these regions of aorta exhibit altered morphology and signaling patterns. Aortas from 15 wild type and 15 FBN1 deficient (FBN1‐/‐) mice were isolated and divided into 4 segments: ascending aorta, arch, proximal and distal thoracic aorta. VVG staining of aortic cross‐sections showed that aortas of FBN1‐/‐ mice have diffuse fragmentation of elastic lamella and decreased elastic lamellar thickness (p=0.005). Increased wall thickness (p=0.002), inner radius (p=0.000), and wall cross‐sectional area (p=0.000) was present in the ascending aorta and arch of FBN1‐/‐ mice. The same area was associated with increased levels of pSMAD3 protein and decreased relative expression of SMAD3 mRNA. More research is needed to determine relationships between TGFβ signaling, distributions of wall stresses, and increased wall stiffness due to elastin fragmentation in aortas of Marfan patients.