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

Detta är en avhandling från Lund University Experimental Science

Sammanfattning: 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 ?4 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 ?2, ?4, ?5, ?2 and ?1. In plaques, the laminin ?1 chain was up-regulated and the laminin ?2 chain down-regulated and in a cell culture system, mimicking the events of VSMC activation, the laminin ?5 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 ?4 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 ?4 LG4-5 inhibited new blood vessel formation both ex vivo as well as in vivo. Purified integrin ?3?1 was shown to bind laminin ?4LG4-5 and is therefore suggested as a potential receptor for laminin ?4LG4-5. 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 ?2 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 ?4 chain, which could enable a sustained activation of the integrin ?7X1?1D. In conclusion laminin isoform transition and processing of chains appear to occur in several of societies major diseases.