Effect of disruption of the cytoskeleton on smooth muscle contraction.

The relationship between passive tension applied to aortic rings and the resulting increase in tissue length was nearly linear over the range of 1 to 15 g. However, even with increasing tissue length, within the range of 1 to 10 g passive tension, the total active force generated upon stimulation was not significantly changed. These observations emphasize the great flexibility of the mechanism(s) underlying the contractile response of vascular smooth muscle with regard to changes in tissue preload and length. Neither the blockade of microtubule polymerization by colchicine nor the blockade of actin polymerization by cytochalasin B significantly changed the slope of the tissue length-preload curve, indicating no effect on the tissues' capacity to stretch at a given preload. With stimulation of the tissue at different levels of stretch, colchicine caused an increase in the initial fast component of active tension development, but partially blocked the secondary slow rise in tension. Cytochalasin B dramatically reduced the total contractile response at each preload studied, and this effect was confined almost exclusively to the secondary slow increase in tension. When tissues were cooled to cause complete dissolution of the microtubule network and then warmed in the presence of colchicine to prevent repolymerization of both the active and stable populations of microtubules, there was also a significant reduction in the slow component of contraction with no effect on the fast response. The partial blockade of synthesis of the microtubule-associated motor protein kinesin by application of an antisense oligonucleotide to aortae in situ or to aortic rings in tissue culture significantly reduced the contractile response to potassium depolarization. The results suggest that the microtubules and the actin filaments of the cytoskeleton play an active role in slow force development as opposed to a solely passive role based on the effect of the static, structural properties of these filaments on mechanical resistance. We propose that a tension-bearing element of the actin-containing cytoskeleton undergoes remodeling to adjust tension within the system. The microtubules could act either through the directed movement of the molecules involved in the transduction process or through the direct action of kinesin-mediated intracytoskeletal interactions in force development that involve a remodeling of the tension-bearing elements of the cytoskeleton.