SEMINAR: The Role of Vascular Basement Membranes in Cerebral Vessel Structural and Functional Integrity

The Seminar: Basement membrane (BM) composition varies with both blood vessel and with tissue type. Of all BM components, the laminin family shows the greatest variability and represents the biological active component of BMs, interacting with a wide repertoire of integrin and non-integrin receptors to control functions such as vessel integrity and permeability. Microvessels of the central nervous system (CNS) have a unique composition of cellular and extracellular matrix layers that collectively constitute the blood-brain barrier. In addition to the endothelial cell monolayer and its underlying BM, cerebral microvessels are ensheathed by astrocyte endfeet and leptomeningeal cells, which contribute to a second BM, the so-called parenchymal BM as it delineates the border to the brain parenchyma. While considerable information is available on the cellular constitutents of the CNS microvessels and their contribution to the BBB, little is known about the BM layers. Our work has shown that endothelial and parenchymal BMs of CNS vessels are structurally and functionally distinct, and has highlighted their importance in the restricted permeability characteristic of the CNS microvessels. In particular, laminin isoforms are heterogeneously localized along the length of the endothelial BM of microvessels and play an important role in defining sites of high and low penetrability by infiltrating cells, such as extravasating leukocytes during inflammation1. In addition, endothelial laminins impact on endothelial stiffness and the ability of the vessels to detect and respond to shear. By contrast, ECM components of the parenchymal border confer tensile strength and as consequence penetration of this border requires focal matrix metalloproteinase (MMP)-2 and MMP-9 activity2. Data will be presented on the biochemical differences of BMs of CNS microvessels, and how vascular laminins and MMP-2 and MMP-9 act to control vascular integrity in the context of leukocyte extravasation1.

1. Wu, C., F. Ivars, P. Anderson, R. Hallmann, D. Vestweber, P. Nilsson, H. Robenek, K. Tryggvason, J. Song, E. Korpos, K. Loser, S. Beissert, E. Georges-Labouesse, & L.M. Sorokin. 2009. Nat Med. 15, 519-27 2. Agrawal, S., Anderson, P., Durbeej, M., van Rooijen, N., Ivars, F., Opdenakker, G., & Sorokin, L. M. 2006. J. Exp. Med. 203, 1007-1019

The Speaker: Lydia Sorokin obtained her PhD from the Physiology Department at the University of Western Australia in receptor-mediated endocytosis and carried out her first postdoctoral position at the Friedrich-Miescher laboratory of the Max-Planck Society in Tübingen, Germany, where she commenced her work on the extracellular matrix. She has spent the last 22 years in Germany and Sweden and is currently professor and director of Pathobiochemistry at the Westfälische Wilhelms University in Münster, Germany. Her interests are the biochemistry, ultrastructure and function of basement membranes, with an emphasis on vascular basement membranes and inflammation, and the role of the ECM in secondary lymphoid organs