Deletion of the Laminin α4 Chain Leads to Impaired Microvessel Maturation

Abstract

The laminin α4 chain, a component of laminin-8 and -9, is expressed in basement membranes, such as those beneath endothelia, the perineurium of peripheral nerves, and around developing muscle fibers. Laminin α4-null mice presented with hemorrhages during the embryonic and neonatal period and had extensive bleeding and deterioration of microvessel growth in experimental angiogenesis, as well as mild locomotion defects. Histological examination of newborn mice revealed delayed deposition of type IV collagen and nidogen into capillary basement membranes, and electron microscopy showed discontinuities in the lamina densa. The results demonstrate a central role for the laminin α4 chain in microvessel growth and, in the absence of other laminin α chains, in the composition of endothelial basement membranes.

We thank Petra Granquist, Maria Laisi, Johanna Isopahkala, Johanna Räisänen, Ulla Mikkonen, and Wanda Ternström for technical assistance; Mats Estonius, Bernt Jones, and Lars-Olof Hansson for assistance with blood analysis; and Manuel Patarroyo and Maureen Ryan for antibodies. We also thank Ulrich Bergmann and Timo Pikkarainen for critical reading of the manuscript.

This work was supported in part by grants from the Novo Nordisk Foundation, the Swedish Medical Research Council, The Swedish Cancer Foundation, EU grant no. QLGI-CT-01131, and the Human Frontier Science Program.

Jill Thyboll and Jarkko Kortesmaa contributed equally to this work.