Expression and Function of Laminins in the Embryonic and Mature Vasculature

Abstract

Endothelial cells of the blood and lymphatic vasculature are polarized cells with luminal surfaces specialized to interact with inflammatory cells upon the appropriate stimulation; they contain specialized transcellular transport systems, and their basal surfaces are attached to an extracellular basement membrane. In adult tissues the basement membrane forms a continuous sleeve around the endothelial tubes, and the interaction of endothelial cells with basement membrane components plays an important role in the maintenance of vessel wall integrity. During development, the basement membrane of endothelium provides distinct spatial and molecular information that influences endothelial cell proliferation, migration, and differentiation/maturation. Microvascular endothelium matures into phenotypically distinct types: continuous, fenestrated, and discontinuous, which also differ in their permeability properties. Development of these morphological and physiological differences is thought to be controlled by both soluble factors in the organ or tissue environment and by cell-cell and cell-matrix interactions. Basement membranes of endothelium, like those of other tissues, are composed of laminins, type IV collagens, heparan sulfate proteoglycans, and nidogens. However, isoforms of all four classes of molecules exist, which combine to form structurally and functionally distinct basement membranes. The endothelial cell basement membranes have been shown to be unique with respect to their laminin isoform composition. Laminins are a family of glycoprotein heterotrimers composed of an alpha, beta, and gamma chain. To date, 5alpha, 4beta, and 3gamma laminin chains have been identified that can combine to form 15 different isoforms. The laminin alpha-chains are considered to be the functionally important portion of the heterotrimers, as they exhibit tissue-specific distribution patterns and contain the major cell interaction sites. Vascular endothelium expresses only two laminin isoforms, and their expression varies depending on the developmental stage, vessel type, and the activation state of the endothelium. Laminin 8 (composed of laminin alpha4, beta1, and gamma1 chains) is expressed by all endothelial cells regardless of their stage of development, and its expression is strongly upregulated by cytokines and growth factors that play a role in inflammatory events. Laminin 10 (composed of laminin alpha5, beta1, and gamma1 chains) is detectable primarily in endothelial cell basement membranes of capillaries and venules commencing 3-4 wk after birth. In contrast to laminin 8, endothelial cell expression of laminin 10 is upregulated only by strong proinflammatory signals and, in addition, angiostatic agents such as progesterone. Other extracellular matrix molecules, such as BM40 (also known as SPARC/osteonectin), thrombospondins 1 and 2, fibronectin, nidogens 1 and 2, and collagen types VIII, XV, and XVIII, are also differentially expressed by endothelium, varying with the endothelium type and/or pathophysiological state. The da...

Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils

“…The data presented also demonstrate that the alterations in the size of LE regions in the vascular BM are directly caused by emigrating neutrophils and are transient in nature, returning toward basal dimensions within 24 h after initiation of transmigration. The latter reinforces the fact that the vascular BM is a dynamic and not a static and rigid structure (6,28). Vascular endothelial cells have been reported to respond rapidly to proinfl ammatory cytokines with altered expressions of the vascular laminin isoforms, laminins 8 and 10, resulting in local changes in the underlying basement membrane (6, 13, 37) and adaptation to the physiological needs of the tissue.…”

“…To investigate the expression of venular BM constituents, cremaster muscles were immunostained for laminin 8 (α4β1γ1 chains) and 10 (α5β1γ1 chains), the principal vascular laminin isoforms (6,(12)(13), in parallel with other key basement membrane components, collagen type IV (25), perlecan (26), and nidogen-2 (27), using a panel of wellcharacterized anti-mouse antibodies (28). Immunostaining of unstimulated whole cremasteric muscles with a rabbit anti-laminin α5 (LN-α5) chain polyclonal antibody (405), detecting the laminin 10 isoform, consistently indicated a dis continuous expression profi le of this matrix protein in venules but not arterioles (both at 20-40 μm in diameter).…”

Endothelial basement membrane laminin 511 is essential for shear stress response

“…In the endothelial cell basement membrane, laminin α4 and α5 chains occur bound to β1 and γ1 chains to form laminins 411 and 511. Laminin 411 is ubiquitously expressed in all endothelial basement membranes from the first stages of tube formation (Hallmann et al , 2005) and has been shown to play a role in angiogenesis in some tissues (Stenzel et al , 2011). By contrast, laminin α5 first appears surrounding arteries when the heart commences to beat (E10) and when blood pressure is initiated, and only much later in basement membranes of microvessels (Sorokin et al , 1997); it has been implicated in immune cell extravasation (Sixt et al , 2001a; Wu et al , 2009).…”

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

“…The alteration of the basement membrane, combined with reduced tenascin-C expression and cellular changes, suggest that the elements of the severe endstage phenotype are already in place in mutants of these ages. The importance of basement membrane integrity in development is widely recognized (Hallmann et al, 2005;Nguyen and Senior, 2006). Furthermore, the deficiency in tenascin-C is of interest because tenascin-C deficient mice show a similar, but weaker, phenotype during postnatal lung development.…”