title: Fibrillins 1 and 2 perform partially overlapping functions during aortic development.
abstract: 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.
authors.affiliation: Laboratory of Genetics and Organogenesis, Hospital for Special Surgery, the Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Carta
authors.forename: Lygia
authors.initials: L
authors.lastname: Pereira
authors.forename: Emilio
authors.initials: E
authors.lastname: Arteaga-Solis
authors.forename: Sui Y
authors.initials: SY
authors.lastname: Lee-Arteaga
authors.forename: Brett
authors.initials: B
authors.lastname: Lenart
authors.forename: Barry
authors.initials: B
authors.lastname: Starcher
authors.forename: Christian A
authors.initials: CA
authors.lastname: Merkel
authors.forename: Marina
authors.initials: M
authors.lastname: Sukoyan
authors.forename: Alexander
authors.initials: A
authors.lastname: Kerkis
authors.forename: Noriko
authors.initials: N
authors.lastname: Hazeki
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D028341:Activins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001011:Aorta / Q000196:embryology*; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003433:Crosses, Genetic; D055515:Cysteine-Rich Protein 61; D003895:Desmosine / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006579:Heterozygote; D017874:Immediate-Early Proteins / Q000378:metabolism; D015151:Immunoblotting; D028322:Inhibin-beta Subunits / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020894:Microfibrils / Q000737:chemistry; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism; D008854:Microscopy, Electron; D008957:Models, Genetic; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D054392:Adipokines
chemical_list: D028341:Activins; D003285:Contractile Proteins; D003432:Cross-Linking Reagents; D055515:Cysteine-Rich Protein 61; D003895:Desmosine; D004549:Elastin; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D017874:Immediate-Early Proteins; D028322:Inhibin-beta Subunits; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D017395:Plasminogen Activator Inhibitor 1; D012313:RNA; C501848:CCN1 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C000605724:Fbn1 protein, mouse; C000605728:Fbn2 protein, mouse; C422405:activin A