Function of contractile and cytoskeletal proteins in smooth muscle: Effects of hypertrophy and age and desmin removal in a transgenic animal

Sammanfattning: In man, the urinary bladder responds to an urinary outflow obstruction with a pronounced dilatation and growth of the bladder wall. This clinical situation can be mimicked in rat by creation of a partial urinary outflow obstruction and the papers included in the present thesis use this animal model to address questions regarding the adaptive changes in the smooth muscle of the growing bladder. In paper I, it was demonstrated that both the relaxing (P2Y) and contractile (P2X) purinergic responses were downregulated in the hypertrophying rat urinary bladder, suggesting that properties of the purinoceptors or steps in the excitation- contraction coupling are altered. In paper II, the kinetics of the contractile machinery in the hypertrophying bladder muscle was examined. Hypertrophy was associated with slower rate of contraction and a slower shortening velocity, which was associated with a change towards more of the 'slow' essential myosin light chain isoform and less of the 'fast' inserted myosin heavy chain. In paper III, it was shown that the contractile properties and cellular concentration of contractile proteins in the urinary bladder were unchanged in old compared to adult rats. These results show that previously reported alterations in the contractile performance of the urinary bladder of old animals do not originate in the contractile system. In paper IV, a transgenic mouse strain lacking the intermediate filament protein desmin was used to examine to mechanical role of this cytoskeletal protein. Smooth muscles from these mice developed less force and were more compliant, suggesting that the intermediate filaments play a role in force transmission. In paper V, the expression of a non-muscle myosin heavy chain was examined in hypertrophying smooth muscle from urinary bladder. The SMemb increased transiently in cells localised outside the smooth muscle bundles. These cells may have a role in the maintenance of the extracellular matrix, provide a source for differentiation into adult muscle cells or produce growth factors. SMemb expression could be a marker for adaptive growth in the non-muscle component of the smooth muscle wall.