Laminins in blood vessel development and disease -functional aspects in angiogenesis, atherosclerosis, and muscular dystrophy

Basement membranes are sheet like extracellular matrices that underlie or surround many cell types. They are crucial for key cellular events such as cell migration, proliferation, survival and differentiation. Vital components of all basement membranes are laminins, heterotrimeric combinations of different laminin chain isoforms. The different laminins and their subunits largely have a developmental and tissue specific distribution. To determine the function of laminin isoforms in pathological conditions, three model diseases were used. Special focus was on the vasculature, but also on the most blood vessel specific laminin chain, the laminin α4 chain. Atherosclerosis is an inflammatory process in large and medium sized arteries. During progression of atherosclerosis the vascular smooth muscle cells (VSMC) in the vessel wall become activated and start to migrate and proliferate. Extracellular matrix molecules are important for this process, but not much was known about VSMC laminin expression in health or disease. Therefore, this was studied in healthy and atherosclerotic vessels. Major laminin chains in VSMC were laminin α2, α4, α5, β2 and γ1. In plaques, the laminin β1 chain was up-regulated and the laminin β2 chain down-regulated and in a cell culture system, mimicking the events of VSMC activation, the laminin α5 chain was also seen to be reduced. Tumour growth and metastasis are both dependent on incorporation of vessels into the tumour. An approach to treat cancers would therefore be to inhibit endothelial cell proliferation and migration. The C-terminal part of the laminin α4 chain, the LG4-5 domain, is proteolytically released. This domain was shown to be retained in the circulation and to reduce endothelial cell migration in vitro. Further studies showed that laminin α4 LG4-5 inhibited new blood vessel formation both ex vivo as well as in vivo. Purified integrin α3β1 was shown to bind laminin α4LG4-5 and is therefore suggested as a potential receptor for laminin α4LG4-5. The extraocular muscles are selectively spared from muscle wasting in some muscular dystrophies, including a mouse model of muscular dystrophy arising from complete absence of laminin α2 chain. This model was used to identify the cause of this exclusion. Immunohistochemical and quantitative PCR studies suggested that extraocular muscles were spared due to high expression of the laminin α4 chain, which could enable a sustained activation of the integrin α7X1β1D. In conclusion laminin isoform transition and processing of chains appear to occur in several of societies major diseases.