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. 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. Elastogenesis is a complex biological process that involves the organized deposition and self-assembly of several macromolecules into microfibrils and elastic fibers (1Mecham R.P. Davis E. Extracellular Matrix Assembly and Structure.in: Yurchenco P.D. Birk D.E. Mecham R.P. Academic Press, Inc., New York1994: 281-314Crossref Google Scholar). Elastic fibers are made of an amorphous core of cross-linked elastin and other molecules and microfibrils; the latter are heterogeneous in composition and can also form macroaggregates devoid of elastin (2Handford P.A. Downing A.K. Reinhardt D.P. Sakai L.Y. Matrix Biol. 2000; 19: 457-470Crossref PubMed Scopus (114) Google Scholar, 3Kielty C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar). Fibrillins 1 and 2 are the main structural components of extracellular microfibrils and the defective gene products in Marfan syndrome (MFS) 3The abbreviations used are: MFS, Marfan syndrome; CCA, congenital contractural arachnodactyly; CYR61, cysteine-rich angiogenic protein 61; Fbn1 and Fbn2, the mouse genes coding for fibrillin-1 and fibrillin-2, respectively; PAI-1, plasminogen activator inhibitor-1; VSMC, vascular smooth muscle cells; MMP, matrix metalloproteinase. and congenital contractural arachnodactyly (CCA), respectively (4Ramirez F. Curr. Opin. Genet. Dev. 1996; 6: 309-315Crossref PubMed Scopus (106) Google Scholar, 5Charbonneau N.L. Ono R.N. Corson G.M. Keene D.R. Sakai L.Y. Birth Defects Res. C Embryo Today. 2004; 72: 37-50Crossref PubMed Scopus (88) Google Scholar). MFS is a pleiotropic disorder of the connective tissue with wide variation in clinical severity (6Pyeritz R.E. Principles and Practice of Medical Genetics.in: Rimoin D.L. Connor J.M. Pyeritz R.E. Korf B.R. 4th Ed. Churchill Livingstone, New York, NY2002: 3977-4020Google Scholar). Cardiovascular manifestations in the form of aortic dilatation, dissection, and rupture contribute significantly to morbidity and mortality in affected individuals. CCA, on the other hand, is a rare condition akin to MFS but with major manifestations confined to the musculoskeletal system (6Pyeritz R.E. Principles and Practice of Medical Genetics.in: Rimoin D.L. Connor J.M. Pyeritz R.E. Korf B.R. 4th Ed. Churchill Livingstone, New York, NY2002: 3977-4020Google Scholar). Fibrillins are large cysteine-rich glycoproteins (∼350 kDa) composed primarily of multiple repeated domains homologous to the calcium binding epidermal growth factor module and of distinct 8-cysteine modules (2Handford P.A. Downing A.K. Reinhardt D.P. Sakai L.Y. Matrix Biol. 2000; 19: 457-470Crossref PubMed Scopus (114) Google Scholar, 3Kielty C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar, 5Charbonneau N.L. Ono R.N. Corson G.M. Keene D.R. Sakai L.Y. Birth Defects Res. C Embryo Today. 2004; 72: 37-50Crossref PubMed Scopus (88) Google Scholar). Fibrillins polymerize into a characteristic beads-on-a-string microfibril structure, which gives rise to the microfibril lattice by lateral association of the individual microfibril polymers and probable association of other structural components. Fibrillins can form homo- or heteropolymeric microfibrils and can interact with integrins, growth factors, several other matrix components, and latent transforming growth factor β-binding proteins. Differential expression of elastic fiber components, dynamic cell-matrix interactions, and microfibril-mediated modulation of signaling molecules account for the diverse architectures and functions of elastic networks during the development and growth of individual organ systems (5Charbonneau N.L. Ono R.N. Corson G.M. Keene D.R. Sakai L.Y. Birth Defects Res. C Embryo Today. 2004; 72: 37-50Crossref PubMed Scopus (88) Google Scholar). The process of aortic media formation is an illustrative example of the interplay between resident cells and elastic fiber components that ultimately results in the highly organized and functionally competent tissue (7Brooke B.S. Karnik S.K. Li D.Y. Trends Cell Biol. 2003; 13: 51-56Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 8Kelleher C.M. McLean S.E. Mecham R.P. Curr. Top. Dev. Biol. 2005; 62: 153-188Crossref Scopus (164) Google Scholar). At about mid-gestation, vascular smooth muscle cells (VSMC) deposit fibrillins and tropoelastin molecules into the surrounding matrix and begin to organize them into elastic fibers. The latter process extends into early neonatal life accompanied by the gradual growth of elastic fibers into mature elastic lamellae that separate parallel layers of quiescent VSMC. The resulting organization of the tunica media into a multilayered structure of alternating VSMC and elastic lamellae (also known as the lamellar unit) is the main determinant of arterial function. Genetic studies in mice have demonstrated that different molecules participate in the various steps responsible for the maturation and function of the arterial wall. Fibulin-5 has been reported to regulate initial assembly of the elastic fiber by providing the molecular bridge between tropoelastin in the pericellular space and integrins on the surface of VSMC, whereas lysyl oxidase-like protein-1 is believed to spatially restrict elastin polymerization by interacting with fibulin-5 (9Yanagisawa H. Davis E.C. Starcher B.C. Ouchi T. Yanagisawa M. Richardson J.A. Olson E.N. Nature. 2002; 415: 168-171Crossref PubMed Scopus (498) Google Scholar, 10Nakamura T. Lozano P.R. Ikeda Y. Iwanaga Y. Hinek A. Y. J. T. Nature. 2002; 415: PubMed Scopus Google Scholar, Y. J. Starcher J.A. Yanagisawa H. J. Li T. Genet. 2004; PubMed Scopus Google Scholar). on the other hand, is to the quiescent phenotype of VSMC as well as to vascular in to D.Y. Davis E.C. Mecham R.P. J. PubMed Scopus Google Scholar, S.K. B.S. A. Li D.Y. 2003; PubMed Scopus Google Scholar). a in vascular and VSMC has also been to fibulin-5 J.A. Davis E.C. Mecham R.P. Li D.Y. Richardson J.A. Olson E.N. Yanagisawa H. Sci. A. 2005; PubMed Scopus Google Scholar). the lysyl has been to the aortic by the extracellular of tropoelastin molecules into the elastic J.M. J. H. 2002; Scopus Google Scholar, Starcher Mecham R.P. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). mouse distinct in the fibrillin-1 gene have been created that the of clinical severity in MFS J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar, D.P. Keene D.R. J. D.L. Sakai L.Y. J. 2004; PubMed Scopus Google Scholar). The the of an in a calcium binding epidermal growth factor and a which in the neonatal form of MFS, and a that of the normal of fibrillin-1 and which in the form of aortic aneurysm in these mice is with morphologically normal elastic fibers between and in the that fibrillin-1 microfibrils a in tissue than aortic development J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar). The that fibrillin-2 is than fibrillin-1 and primarily during development to a for in matrix assembly H. F. J. Cell Biol. PubMed Scopus Google Scholar). However, the of by the that of fibrillin-2 in mice affected signaling and formation but had on E. Sakai F. J. Cell Biol. PubMed Scopus Google Scholar). the studies in in MFS, the of the of fibrillin-1 microfibrils during development. The to elucidate the contribution of fibrillin-1 to organogenesis, to aortic by a of mice that completely lacks of these mice also to or fibrillins 1 and 2 have functions in organ formation by aortic development in the of of Fbn1 and Fbn2 null mice. The results of these studies are the to the of fibrillin-1 in the maturation of the aortic and of fibrillin-rich microfibrils in tissue development. are also the to demonstrate between fibrillins 1 and 2 in matrix formation and to the for functions in of Fbn1 and of the as well as and of mouse cells and of mice as J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar). of the Fbn1 gene of which the and the coding with the and the gene an cell into and mice with the of the and on tissue and mouse respectively Keene D.R. Sakai L.Y. F. J. Cell Biol. 2000; PubMed Scopus Google Scholar). by the and and for 1 for 1 and for 1 and for 1 for 1 for 1 The of the different in the from the between null Fbn1 and Fbn2 mice a of as and and mice as J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar). and with and and with for elastic fibers and for tissue and in and to and and of the with or for 1 by with Inc., for with to the and with tissue a Inc., and with an and and neonatal for 1 Cell layers into and for in 2 and The for the to with and the and the microfibrils visualized by electron microscopy after or A. Keene D.R. Ono R.N. Reinhardt D.P. Sakai L.Y. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). and from embryos and mice. between and of protein as by in of to Starcher and M. Res. PubMed Scopus Google Scholar). from for and and for as of to protein and a as on protein from of and mice or from the tissue of mice in Inc., used as a in a and an The to 1 in or in mouse and in a or in the of in and for 1 products visualized by the and with Inc., of the results the a as from the of and mice the Inc., on from the of and Fbn1 null mice the and and and and with and in a of that of of and of in with an initial for by for and for 1 data the system and with the system from the which is the PubMed Scopus Google Scholar). of the results with the a as of in and Fbn1 null created by part of the 1 to the of fibrillin-1 during development and growth of the by of neonatal tissue and of media from mouse documented of Fbn1 gene in mice C and The data also the that fibrillin-2 for of fibrillin-1 of aortic and mice the mice and all mice died the 2 of life from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse. aortic aneurysm with documented or affected with of the and the and data all mice displayed and and and of the and data aneurysm in Fbn1 null mice involved the than the of the a with the phenotype of the other Fbn1 mice and MFS (6Pyeritz R.E. Principles and Practice of Medical Genetics.in: Rimoin D.L. Connor J.M. Pyeritz R.E. Korf B.R. 4th Ed. Churchill Livingstone, New York, NY2002: 3977-4020Google Scholar, J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar). of or of aortic from mice revealed a of the lamellar in the medial layer Elastic fibers had an and and and whereas VSMC had with cells and surrounding matrix and revealed of in the aortic lamellae However, that of mice, such as matrix and T. Sakai L.Y. F. Sci. A. PubMed Scopus Google virtually in the aorta of and data VSMC expression of in the aortic tissue of mice to mice. the in and of mice, with the of structural between the and medial layers E.C. J. Cell Sci. PubMed Google Scholar). the of the lamellar to as in other Fbn1 mice, but involved the aorta J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. 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Consistent with these in mice and the of vascular manifestations in the of the aortic in and mice to that of that fibrillin-2 is for tissue development or functionally with fibrillin-1 To between these the of fibrillin-rich microfibrils during we after birth the of and and that the of mice the for a between the in to that of extracellular microfibrils is with The latter by the of embryos and of which the of of Fbn1-/-;Fbn2-/- embryos to after from of embryos impaired or in the medial layer of the Fbn1-/-;Fbn2-/- aorta compared with the The in the of Fbn1-/-;Fbn2-/- with of Fbn1-/- or embryos and and data Fbn1 and Fbn2 null with of and with of and with of and in a of illustrative of and Fbn1-/-;Fbn2-/- embryos of from the embryos as well as from an null and a Fbn1+/-;Fbn2-/- organization of the vessel in the In contrast to and mice, a from the for the Fbn1+/-;Fbn2-/- birth that between the fibrillins during development is a gene in which Fbn2 a of the medial layer of Fbn1+/-;Fbn2-/- embryos that the elastic fibers are than control with the of matrix assembly in the aorta of Fbn1+/-;Fbn2-/- for these is that elastic fiber formation is by the of microfibrils into the extracellular space of the of the a contribution of fibrillin-2 molecules expression of Fbn2 is the and expression of Fbn1 is significantly than is C.M. McLean S.E. Mecham R.P. Curr. Top. Dev. Biol. 2005; 62: 153-188Crossref Scopus (164) Google Scholar, H. F. J. Cell Biol. PubMed Scopus Google Scholar). is that microfibrils a functionally distinct in the To or is a structural for the function of fibrillin-2, microfibrils from and neonatal and by electron Analysis of the to the of fibrillin-2 In contrast to the polymers from and and of microfibrils from that fibrillin-2 as an structure to of which fibrillin-1 and fibrillin-2, or whereas which fibrillin-2 but and revealed a electron to the of in the microfibril electron has been in of microfibrils from or from fibrillin-1 molecules Keene D.R. Sakai L.Y. F. J. Cell Biol. 2000; PubMed Scopus Google and in of microfibrils from The of the fibrillin-2 the of a specialized function of microfibril during the early of Genetic studies in mice used to the diverse of matrix components, fibrillins 1 and to the development and function of the are main of these we have that of Fbn1 gene expression in mice results in neonatal to structural of elastic that are normally to and such as the and results are with the from of mice with other Fbn1 that the main of fibrillin-1 microfibrils is to impart structural to elastic during life utero J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar). However, we demonstrated that the aortic phenotype of mice is for by maturation of the vessel in the of normal levels of elastin and that tissue repair are during aneurysm significantly the that fibrillin-1 is involved in tissue during life. by mice with deficiency of we documented that of or Fbn1 in an Fbn2 null the that fibrillin-2 is for of matrix assembly and development C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar, E. Sakai F. J. Cell Biol. PubMed Scopus Google Scholar). In from these mice for the that elastic fiber formation The of the aorta the that between resident cells and the elastic matrix during and organ growth (7Brooke B.S. Karnik S.K. Li D.Y. Trends Cell Biol. 2003; 13: 51-56Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 8Kelleher C.M. McLean S.E. Mecham R.P. Curr. Top. Dev. 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PubMed Scopus Google Scholar, F. Res. PubMed Scopus Google Scholar). In contrast to the of tissue repair are in the aorta of mice during aneurysm The of and of which are by transforming growth to matrix formation PubMed Google Scholar). of is also with the of signaling in the to vascular J. PubMed Scopus Google Scholar). is in with known function to cell and regulate matrix as well as with the of of large in null mice Biol. 2002; PubMed Scopus Google Scholar, J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). other we that the between of tissue repair and of for in null mice the progression of vascular in mouse of from neonatal of MFS that the process of elastic fiber in the of MFS the contribution of a impaired which is to poorly to and the of of matrix which are to progression and by transforming growth T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar, F. Res. PubMed Scopus Google Scholar, P.A. D.E. F. Sakai L.Y. Genet. 2003; PubMed Scopus Google Scholar). The involvement of in the is with data that and than normal levels of the which has been to as a into Y. H. Y. M. H. T. Iwanaga H. M. T. A. T. T. Cell Biol. 2004; 6: PubMed Scopus Google Scholar). by is the of aneurysm in the aorta of null mice than in the aortic which of the is to that of mice aortic with aortic aneurysm, a congenital of in which the of the aortic matrix and VSMC is believed to responsible for aortic that by Curr. Opin. 2004; 19: PubMed Scopus Google Scholar). of elastic fiber formation to the that microfibrils regulate by providing the that tropoelastin deposition (1Mecham R.P. Davis E. Extracellular Matrix Assembly and Structure.in: Yurchenco P.D. Birk D.E. Mecham R.P. Academic Press, Inc., New York1994: 281-314Crossref Google Scholar). The that fibrillin-2 that of fibrillin-1 and with early fibrillin-2 microfibrils as the of elastic fiber assembly H. F. J. Cell Biol. PubMed Scopus Google Scholar). to Fbn2 null mice to and to a to signaling E. Sakai F. J. Cell Biol. PubMed Scopus Google Scholar). that fibrillin-2 is in matrix assembly or fibrillin-1 for during development C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar, E. Sakai F. J. Cell Biol. PubMed Scopus Google Scholar). The that virtually all Fbn1-/-;Fbn2-/- embryos and half of the Fbn1+/-;Fbn2-/- embryos to development the latter also that fibrillin-1 for the of fibrillin-2 is on the of fibrillin-1 molecules into the are that gene Elastic tissue formation by the of extracellular or fibrillin-2 microfibrils a functionally distinct in the fibrillin-1 and fibrillin-2 are homologous molecules with between them (2Handford P.A. Downing A.K. Reinhardt D.P. Sakai L.Y. Matrix Biol. 2000; 19: 457-470Crossref PubMed Scopus (114) Google Scholar, 3Kielty C.M. Sherratt M.J. Shuttleworth C.A. J. Cell Sci. 2002; 115: 2817-2828Crossref PubMed Google Scholar, 5Charbonneau N.L. Ono R.N. Corson G.M. Keene D.R. Sakai L.Y. Birth Defects Res. C Embryo Today. 2004; 72: 37-50Crossref PubMed Scopus (88) Google the and with the of microfibrils in of and fibrillin-1 molecules Keene D.R. Sakai L.Y. F. J. Cell Biol. 2000; PubMed Scopus Google Scholar). that the of fibrillin-1 and fibrillin-2 also microfibril structure tissue development. the of microfibrils in and in the of the aortic in from these and of that fibrillin-2 functions during matrix formation and tissue development by distinct with other matrix components, surrounding and/or signaling by a structure, which an or by a which is visualized as the electron to the of In a is to from and gene function studies in mice with to different matrix components participate in the development and function of the aortic (9Yanagisawa H. Davis E.C. Starcher B.C. Ouchi T. Yanagisawa M. Richardson J.A. Olson E.N. Nature. 2002; 415: 168-171Crossref PubMed Scopus (498) Google Scholar, 10Nakamura T. Lozano P.R. Ikeda Y. Iwanaga Y. Hinek A. Y. J. T. Nature. 2002; 415: PubMed Scopus Google Scholar, Y. J. Starcher J.A. Yanagisawa H. J. Li T. Genet. 2004; PubMed Scopus Google Scholar, D.Y. Davis E.C. Mecham R.P. J. PubMed Scopus Google Scholar, S.K. B.S. A. Li D.Y. 2003; PubMed Scopus Google Scholar, J.A. Davis E.C. Mecham R.P. Li D.Y. Richardson J.A. Olson E.N. Yanagisawa H. Sci. A. 2005; PubMed Scopus Google Scholar, J.M. J. H. 2002; Scopus Google Scholar, Starcher Mecham R.P. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Keene D.R. Ono Reinhardt D.P. Sakai L.Y. T. F. Genet. PubMed Scopus Google Scholar, T. Sakai L.Y. F. Sci. A. PubMed Scopus Google Scholar). fibrillin-1 or is absolutely required for the initial assembly of the elastic by with other matrix components, and/or signaling is of The of fibrillin-2 overlaps in part with that of the function of which is to the maturation of the aortic during development and neonatal is also to impart structural to the tissue. Fibulin-5 and lysyl oxidase-like protein-1 contribute to of than whereas elastin the as in the development and maturation of the elastic and in structural lysyl the aortic matrix during development. studies of mice with combined of different elastic fiber components with the of molecular these extracellular the of these and other H. and for the of the and F. and for and for with the and for the