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Fibrillins 1 and 2 perform partially overlapping functions during aortic development.

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.

Pubmed ID: 16407178 RIS Download

Mesh terms: Activins | Alleles | Animals | Aorta | Cells, Cultured | Contractile Proteins | Cross-Linking Reagents | Crosses, Genetic | Cysteine-Rich Protein 61 | Desmosine | Elastin | Fibrillin-1 | Fibrillin-2 | Fibrillins | Fibroblasts | Genotype | Heterozygote | Immediate-Early Proteins | Immunoblotting | Inhibin-beta Subunits | Intercellular Signaling Peptides and Proteins | Mice | Mice, Transgenic | Microfibrils | Microfilament Proteins | Microscopy, Electron | Models, Genetic | Phenotype | Plasminogen Activator Inhibitor 1 | RNA

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Associated grants

  • Agency: NIAMS NIH HHS, Id: R01 AR042044
  • Agency: NIAMS NIH HHS, Id: P01 AR049698
  • Agency: NIAMS NIH HHS, Id: R01 AR042044-13
  • Agency: NIGMS NIH HHS, Id: F31 GM018511-04
  • Agency: NIGMS NIH HHS, Id: F31 GM018511

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