Published Online
on May 14, 2007

A more recent version of this article appeared on May 29, 2007

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Submitted on July 24, 2006
Accepted on March 13, 2007

Biglycan Deficiency Causes Spontaneous Aortic Dissection and Rupture in Mice

Anne-Marie Heegaard MD, PhD^*, Alessandro Corsi MD, PhD, Carl Christian Danielsen MD, Karina L. Nielsen PhD, Henrik L. Jorgensen MD, PhD, Mara Riminucci MD, PhD, Marian F. Young PhD, and Paolo Bianco MD

From the Department of Pharmacology and Pharmacotherapy (A.H.), Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark; Nordic Bioscience A/S (A.H., K.L.N.), Herlev, Denmark; Department of Experimental Medicine and Pathology (A.C., P.B.), Università La Sapienza, Rome, Italy; Department of Connective Tissue Biology (C.C.D.), Institute of Anatomy, University of Aarhus, Aarhus, Denmark; Department of Clinical Biochemistry (H.L.J.), Bispebjerg University Hospital, Copenhagen, Denmark; Department of Experimental Medicine (M.R.), Università dell’Aquila, L’Aquila, Italy; Parco Scientifico Biomedico San Raffaele (M.R., P.B.), Rome, Italy; Craniofacial and Skeletal Diseases Branch (M.F.Y.), National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.

^* To whom correspondence should be addressed. E-mail: amhe{at}farma.ku.dk.

Background--For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine-rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan-deficient male mice died suddenly within the first 3 months of life.

Methods and Results--Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender-related response to stress in the development of this vascular catastrophe only in male mice.

Conclusions--The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.

Key words: aneurysm • biglycan • gene targeting

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