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Molecular and Cellular Biology, October 2001, p. 7025-7034, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.7025-7034.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Perinatal Lethality and Endothelial Cell Abnormalities in Several Vessel Compartments of Fibulin-1-Deficient Mice

Günter Kostka,1 Richard Giltay,1 Wilhelm Bloch,2 Klaus Addicks,2 Rupert Timpl,1,* Reinhard Fässler,1,3 and Mon-Li Chu4

Max-Planck-Institut für Biochemie, D-82152 Martinsried,1 and Institute for Anatomy, University of Cologne, D-50931 Cologne,2 Germany; Department of Experimental Pathology, Lund University, S-22185 Lund, Sweden3; and Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 191074

Received 31 May 2001/Accepted 11 July 2001

The extracellular matrix protein fibulin-1 is a distinct component of vessel walls and can be associated with other ligands present in basement membranes, microfibrils, and elastic fibers. Its biological role was investigated by the targeted inactivation of the fibulin-1 gene in mice. This led to massive hemorrhages in several tissues starting at midgestation, ultimately resulting in the death of almost all homozygous embryos upon birth. Histological analysis demonstrated dilation and ruptures in the endothelial lining of various small vessels but not in that of larger vessels. Kidneys displayed a distinct malformation of glomeruli and disorganization of podocytes. A delayed development of lung alveoli suggested impairment in lung inflation. Immunohistology demonstrated the absence of fibulin-1 in its typical localizations but no aberrant patterns for several other extracellular matrix proteins. Electron microscopy revealed intact basement membranes but very irregular cytoplasmic processes of capillary endothelial cells in the organs that were most severely affected. Absence of fibulin-1 caused considerable blood loss but did not compromise blood clotting. The data indicate a strong but restricted abnormality in some endothelial compartments which, together with some kidney and lung defects, may be responsible for early death.

* Corresponding author. Mailing address: Max-Planck-Institut für Biochemie, Am Klopferspitz 18A, D-82152 Martinsried, Germany. Phone: 49 (0)89 8578 2440. Fax: 49 (0)89 8578 2422. E-mail: Timpl{at}biochem.mpg.de.

Molecular and Cellular Biology, October 2001, p. 7025-7034, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.7025-7034.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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