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J. Biol. Chem., Vol. 281, Issue 12, 8016-8023, March 24, 2006

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Fibrillins 1 and 2 Perform Partially Overlapping Functions during Aortic Development^*

Luca Carta¹, Lygia Pereira¹, Emilio Arteaga-Solis^¶, Sui Y. Lee-Arteaga, Brett Lenart, Barry Starcher^||, Christian A. Merkel, Marina Sukoyan, Alexander Kerkis, Noriko Hazeki^**, Douglas R. Keene^**, Lynn Y. Sakai^**, and Francesco Ramirez²

From the Laboratory of Genetics and Organogenesis, Hospital for Special Surgery, the Weill Medical College of Cornell University, New York, New York 10021, Departmento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil, ^¶Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, ^||University of Texas Health Science Center, Tyler, Texas 75708, ^**Shriners Hospitals for Children and Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239, and CEINGE-Biotecnologie Avanzate, 80131 Naples, Italy

Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Fbn1^-/- mice died soon after birth from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse. Analysis of the neonatal Fbn1^-/- aorta documented a disorganized and poorly developed medial layer but normal levels of elastin cross-links. Transcriptional profiling revealed that aneurysm progression in Fbn1 null mice is accompanied by unproductive up-regulation of gene products normally involved in tissue repair and vascular integrity, such as plasminogen activator inhibitor-1, activin A, and cysteine-rich angiogenic protein 61. In contrast to Fbn1^-/- mice, Fbn2 null mice had a well developed and morphologically normal aortic wall. However, virtually all Fbn1^-/-;Fbn2^-/- embryos and about half of the Fbn1^+/-;Fbn2^-/- embryos died in utero and displayed a significantly more severe vascular phenotype than Fbn1^-/- mice. Consistent with a specialized function of fibrillin-2, electron microscopy visualized ultrastructurally different microfibrils in Fbn1 null compared with control cell cultures. Collectively, these data demonstrate that involvement of fibrillin-2 in the initial assembly of the aortic matrix overlaps in part with fibrillin-1 and that continued fibrillin-1 deposition is absolutely required for the maturation and function of the vessel during neonatal life.

Received for publication, October 26, 2005 , and in revised form, December 16, 2005.

^* This work was supported by National Institutes of Health Grants AR42044, AR48111, and AR049698, by the Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, the Shriners Hospitals for Children, and the James D. Farley family and the St. Giles Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to the work.

² To whom correspondence should be addressed: Child Health Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, 89 French St., New Brunswick, NJ 08901. Tel.: 732-235-9534; Fax: 732-235-9333; E-mail: ramirefr{at}umdnj.edu.

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