期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 12, 页码 8016-8023出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M511599200
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资金
- NIAMS NIH HHS [R01 AR042044, P01 AR049698, R01 AR042044-13] Funding Source: Medline
- NIGMS NIH HHS [F31 GM018511-04, F31 GM018511] Funding Source: Medline
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.
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