Perinatal lethality and endothelial cell abnormalities in several vessel compartments of fibulin-1-deficient mice

The extracellular matrix protein fibulin-1 is a distinct component of vesse l walls and can be associated with other ligands present in basement membra nes, microfibrils, and elastic fibers. Its biological role was investigated by the targeted inactivation of the fibulin-1 gene in mice. This led to ma ssive hemorrhages in several tissues starting at midgestation, ultimately r esulting in the death of almost all homozygous embryos upon birth. Histolog ical analysis demonstrated dilation and ruptures in the endothelial lining of various small vessels but not in that of larger vessels. Kidneys display ed 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 loca lizations but no aberrant patterns for several other extracellular matrix p roteins. Electron microscopy revealed intact basement membranes but very ir regular 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 stron g but restricted abnormality in some endothelial compartments which, togeth er with some kidney and lung defects, may be responsible for early death.