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(Circulation. 2006;114:I-371 – I-377.)
© 2006 American Heart Association, Inc.

Surgery for Aortic and Peripheral Vascular Disease

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

Maria Nataatmadja, MDSc, PhD; Jennifer West, RN; Malcolm West, MD, PhD, FRACP

From the Department of Medicine, The University of Queensland, Prince Charles Hospital, Brisbane, Australia; Department of Medicine; The University of Queensland, Prince Charles Hospital, Brisbane, Australia; and the Department of Medicine, The University of Queensland, Prince Charles Hospital, Brisbane, Australia.

Correspondence to Malcolm West, Department of Medicine, The University of Queensland, Prince Charles Hospital, Brisbane 4032, Australia. E-mail malcolm.west{at}mailbox.uq.edu.au

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 (TGFß1 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 TGFß1 to 3, hyaluronan, and CD34-positive microcapillaries in MFS aneurysm compared with control. There was increased expression of TGFß1 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 ß-3 integrin at the leading edge of migration in MFS indicating altered directional migration. Western blot showed increased expression of TGFß1 to 3 in MFS but no change in expression of CD44, MT1-MMP, or ß-3 integrin compared with controls.

Conclusions— There was overexpression of TGF-ß 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.

Key Words: aneurysm • cell migration • circulating progenitor cells • hyaluronan • Marfan syndrome • transforming growth factor-ß