Overexpression of Transforming Growth Factor-β Is Associated With Increased Hyaluronan Content and Impairment of Repair in Marfan Syndrome Aortic Aneurysm

Abstract

Background— Marfan syndrome (MFS), a condition caused by fibrillin-1 gene mutation is associated with aortic aneurysm that shows elastic lamellae disruption, accumulation of glycosaminoglycans, and vascular smooth muscle cell (VSMC) apoptosis with minimal inflammatory response. We examined aneurysm tissue and cultured cells for expression of transforming growth factor-beta1 to -beta3 (TGFβ1 to 3), hyaluronan content, apoptosis, markers of cell migration, and infiltration of vascular progenitor cells (CD34). Methods and Results— MFS aortic aneurysm (6 males, 5 females; age 8 to 78 years) and normal aorta (5 males, 3 females; age 22 to 56 years) were used. Immunohistochemistry showed increased expression of TGFβ1 to 3, hyaluronan, and CD34-positive microcapillaries in MFS aneurysm compared with control. There was increased expression of TGFβ1 to 3 and hyaluronan in MFS cultured VSMCs, adventitial fibroblasts (AF), and skin fibroblasts (SF). Apoptosis was increased in MFS (VSMC: mean cell loss in MFS 29%, n of subjects=5, versus control 8%, n=3, P <0.05; AF: 28%, n=5 versus 7%, n=5, P <0.05; SF: 29%, n=3 versus 4%, n=3, not significant). In MFS, there was a 2-fold increase in adventitial microcapillaries containing CD34-positive cells compared with control tissue. Scratch wound assay showed absence of CD44, MT1-MMP, and β-3 integrin at the leading edge of migration in MFS indicating altered directional migration. Western blot showed increased expression of TGFβ1 to 3 in MFS but no change in expression of CD44, MT1-MMP, or β-3 integrin compared with controls. Conclusions— There was overexpression of TGF-β in MFS associated with altered hyaluronan synthesis, increased apoptosis, impaired progenitor cell recruitment, and abnormal directional migration. These factors limit tissue repair and are likely to contribute to aneurysm development.

TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice

“…Studies using transgenic mouse models of Marfan syndrome showed a critical pathogenic role for increased TGF-β signaling in promoting abnormal vessel remodeling, dilatation, and aneurysm expansion (6). The results were confirmed by studies showing upregulation of TGF-β signaling in patients with Marfan disease and by the identification of TGFBR1 and TGBR2 gene mutations in patients with Loeys-Dietz syndrome, thought to be responsible for increased TGF-β activity (7)(8)(9)(10). These studies have led at least some investigators to suggest that monogenic disorders such as Marfan and Loeys-Dietz syndromes are good genetic models for the pathogenesis of other forms of aortic aneurysm (11).…”

“…The results seemed at odds with data showing increased TGF-β signaling as a driving force in the pathogenesis of Marfan syndrome (7,9,10), confirmed later by mechanistic studies showing that inhibition of TGF-β signaling prevents vessel dilatation and aneurysm formation in a mouse model of Marfan disease (6). We therefore used 2 different anti-TGF-β antibodies, including the same anti-TGF-β antibody (AB-100-NA, R&D Systems) shown to inhibit aortic aneurysm formation in a mouse model of Marfan disease (6).…”

Co-expression of FBN1 with mesenchyme-specific genes in mouse cell lines: implications for phenotypic variability in Marfan syndrome

“…Fibrillin-1 is the major structural component of the extracellular microfibrils of the ECM 10 and also seems to be involved in sequestering the growth factor TGFb in inactive form. 5,11,12 In adults, mesenchymal cells derive from stem cells residing in the bone marrow and mesenchymal tissues. 13,14 These stem cells retain the ability to differentiate into cells of connective tissue lineages, including adipocytes, osteoblasts, chondrocytes, smooth and skeletal muscle, endothelial cells of blood vessels and fibroblasts (reviewed in Barry and Murphy 14 ).…”

Rôle du TGFβ dans un modèle d’anévrisme de l’aorte abdominale chez la souris

“…Le [3,4]. Ces données proviennent essentiellement d'études menées chez les patients atteints du syndrome de Marfan dont la physio-1 Syndrome de Marfan : maladie génétique à transmission autosomique dominante due à une altération du tissu conjonctif.…”

“…De façon schématique, les anévrismes syndromiques, qui correspondent aux formes familiales rencontrées dans le syndrome de Marfan 1 ou le syndrome de Loeys-Dietz 2 [2] se distinguent des formes non syndromiques, beaucoup plus fréquentes et qui compliquent les lésions athéromateuses. Plusieurs travaux menés chez l'animal et chez l'homme suggèrent que le TGF (transforming growth factor b) participe au développement de l'anévrisme [3,4]. Ces données proviennent essentiellement d'études menées chez les patients atteints du syndrome de Marfan dont la physio-1 Syndrome de Marfan : maladie génétique à transmission autosomique dominante due à une altération du tissu conjonctif.…”