Role of laminins in physiological and pathological angiogenesis PATRICIA SIMON-ASSMANN*, GERTRAUD OREND, ELMINA MAMMADOVA-BACH, CAROLINE SPENLÉ and OLIVIER LEFEBVRE INSERM, U682 and Université de Strasbourg, Strasbourg, France ABSTRACT The interaction of endothelial cells and pericytes with their microenvironment, in par- ticular with the basement membrane, plays a crucial role during vasculogenesis and angiogenesis. In this review, we focus on laminins, a major family of extracellular matrix molecules present in basement membranes. Laminins interact with cell surface receptors to trigger intracellular sig- nalling that shapes cell behaviour. Each laminin exerts a distinct effect on endothelial cells and pericytes which largely depends on the adhesion receptor profile expressed on the cell surface. Moreover, proteolytic cleavage of laminins may affect their role in angiogenesis. We report in vitro and in vivo data on laminin-111, -411, -511 and -332 and their associated signalling that regulates cell behaviour and angiogenesis under normal and pathological conditions. We also discuss how tissue-specific deletion of laminin genes affects the behaviour of endothelial cells and pericytes and thus angiogenesis. Finally, we examine how coculture systems with defined laminin expression contribute to our understanding of the roles of laminins in normal and pathological vasculogenesis and angiogenesis. KEY WORDS: laminin, basement membrane, vasculogenesis, angiogenesis, cancer Introduction The lumen of blood vessels is lined by endothelial cells (EC) that interact with a subendothelial basement membrane (BM) that is composed of a complex of several matrix proteins (Fig. 1; Eble and Niland, 2009), and contains growth factors and proteases. The interaction of EC with this microenvironment, especially with the BM components, plays an essential role during angiogenic processes (Ingberg, 1992). During development, blood vessels are formed by two distinct processes described as vasculogenesis and angiogenesis. Vasculogenesis characterizes the generation of vessels from mesodermally derived angioblasts. Angiogenesis describes the formation of vessels through sprouting from a pre- existing plexus (Risau and Flamme, 1995). Both events involve cell migration, proliferation and extracellular matrix (ECM) remodelling. Angiogenesis is also an essential event in tumour growth and me- tastasis. Similar to physiological angiogenesis, tumour angiogenesis is regulated by BM molecules in particular upon break-down and reconstitution of the vascular BM during tumour progression. Cells within a tumour can promote angiogenesis, e.g. by secretion of soluble and insoluble angiogenic factors as well as by modulating protease activities. In addition to soluble factors such as growth Int. J. Dev. Biol. 55: 455-465 doi: 10.1387/ijdb.103223ps www.intjdevbiol.com *Address correspondence to: Patricia Simon-Assmann. INSERM, U682, 3 avenue Molière, 67200 Strasbourg, France. Fax: 33-(0)3-88-26-35-38. e-mail: Patricia.Simon-Assmann@inserm.fr - web: http://u682-inserm.u-strasbg.fr Final, author-corrected PDF published online: 27 July 2011. ISSN: Online 1696-3547, Print 0214-6282 © 2011 UBC Press Printed in Spain Abbreviations used in this paper: BM, basement membrane; CAM, chick chorioallan- toic membrane assay; EC, endothelial cells; ECM, extracellular matrix; EHS, Engelbreth-Holm-Swarm; FGF, fbroblast growth factor; FGFR, fbroblast growth factor receptor; LM, laminin; MMP, matrix metalloproteinase; PDGF-(BB), platelet-derived growth factor-(BB); PDGF-Rb, platelet-derived growth factor receptor b; PTFE, polytetrafuoroethylene; TGFb, transforming growth factor b; VE-cadherin, vascular endothelial-cadherin; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. factors and chemokines that can support or inhibit angiogenesis, matrix molecules of the BM also play a decisive role in angioge- nesis. For example the interaction of EC with intact collagen IV promote angiogenesis whereas proteolytic fragments of collagen IV and other collagens counteract this process (for reviews see Kalluri, 2003; Davis and Senger, 2005; Hallmann et al., 2005). In this review we will focus on the role of LM in vasculogenesis and angiogenesis in normal tissue homeostasis and diseases. LM are multifunctional matrix molecules that are widely expressed for- ming the major scaffold of the BM (Yurchenco and Patton, 2009). LM display organ, site and developmental specifcity (Miner and Yurchenco, 2004). They are cross-shaped trimers which are as- sembled into a triple-stranded coiled-coil structure. Up to 15 distinct