Atherosclerosis is a disease characterized by lesions located in the wall of blood vessels. These lesions are induced by disorders that injure the endothelium, such as hypertension, diabetes, and smoking. Monocytes, T lymphocytes, and platelets, which are three formed elements that circulate in the bloodstream, act on the damaged vascular endothelium. They generate chemotactic factors and mitogens that modify the structure of the surrounding smooth muscle cells. The smooth muscle cells lose most of their thick and thin filaments and develop an extensive rough endoplasmic reticulum and Golgi complex. These cells migrate to the subendothelial space (i.e., the tunica media of the artery), proliferate, and participate in the formation of the fatty lesions or fibrous plaques that characterize atherosclerosis. Inhibition or downregulation of Rho kinase (ROK) has been shown to promote regression of atherosclerotic-like lesions in an animal model. The mechanism or mechanisms underlying this beneficial effect of ROK inhibition are unclear but may be related to regulation of both endothelial permeability and monocyte migration by ROK. That is, hyperactivity of ROK has been implicated in various pathological conditions, including increased transendothelial permeability (perhaps secondary to increased actomyosin activity), whereas inhibition of ROK has been shown to decrease transendothelial migration of monocytes and neutrophils.

Smooth muscle contains large amounts of connective tissue composed of extensible elastin fibrils and inextensible collagen fibrils. This extracellular matrix can withstand high distending forces or loads, which is responsible for the passive length-tension curve measured in relaxed tissues. The matrix also limits organ volume.

The length-tension curves for smooth and skeletal muscle are very similar when lengths are normalized to the optimal length for development of force (L0). However, the length-tension curves of striated and smooth muscle differ quantitatively. For example, smooth muscle cells shorten more than skeletal muscle cells do. Additionally, smooth muscle is characteristically only partially activated, and the peak isometric force attained varies with the stimulus. In skeletal muscle, the stimulus (i.e., action potential) always produces a full twitch contraction. Smooth muscle can generate active force comparable to that of skeletal muscle, even though smooth muscle contains only about a fourth as much myosin. This does not imply that the cross-bridges in smooth muscle have greater force-generating capacity. Instead, active cross-bridges in smooth muscle are much more likely to be in the attached force-generating configuration because of their slow cycling kinetics.
Atherosclerosis isadiseasecharacterizedbylesionslocatedinthewallofbloodvessels.Thelesionsareinducedbydisordersthatinjuretheendothelium,suchashypertension,diabetes,andsmoking.Threeformedelements(monocytes,Tlymphocytes,andplatelets)thatcirculateinthebloodstreamactonthedamagedvascularendothelium.There,theygeneratechemotacticfactorsandmitogensthatmodifythestructureofthesurroundingsmoothmusclecells.ThelatterlosemostoftheirthickandthinfilamentsanddevelopanextensiveroughendoplasmicreticulumandGolgicomplex.Thesecellsmigratetothesubendothelialspace(i.e.,thetunicamediaoftheartery),proliferate,andparticipateinformationofthefattylesionsorthefibrousplaquesthatcharacterizeatherosclerosis.InhibitionordownregulationofRhokinase(ROK)hasbeenshowntopromoteregressionofatherosclerotic-likelesionsinananimalmodel.ThemechanismormechanismsunderlyingthisbeneficialeffectofROKinhibitionareunclearbutmayberelatedtoregulationofbothendothelialpermeabilityandmonocytemigrationbyROK.Thatis,hyperactivityofROKhasbeenimplicatedinvariouspathologicalconditions,includingincreasedtransendothelialpermeability(perhapssecondarytoincreasedactomyosinactivity),whereasinhibitionofROKhasbeenshowntodecreasetransendothelialmigrationofmonocytesandneutrophils.
Biophysical Properties of Smooth Muscle
Smooth muscle contains large amounts of connective tissue composed of extensible elastin fibrils and inextensible collagen fibrils. Because this extracellular matrix can withstand high distending forces or loads, it is responsible for the passive length-tension curve measured in relaxed tissues. This ability of the matrix also limits organ volume.
When lengths are normalized to the optimal length for development of force (i.e., L0), the length-tension curves for smooth and skeletal muscle are very similar (
Fig. 14.15 ). However, the length-tension curves of striated and smooth muscle differ quantitatively. For example, smooth muscle cells shorten more than skeletal muscle cells do. In addition, smooth muscle is characteristically only partially activated, and the peak isometric force attained varies with the stimulus. In skeletal muscle the stimulus (i.e., action potential) always produces a full twitch contraction. Smooth muscle can generate active force comparable to that of skeletal muscle, even though smooth muscle contains only about a fourth as much myosin. This does not imply that the cross-bridges in smooth muscle have greater force-generating capacity. Instead, active cross-bridges in smooth muscle are much more likely to be in 2.4 2.0 1.6 1.2 0.8 0.4 0.6 0.8 1.0 1.2 Po = 2.22 ± 0.17 × 106 dynes/cm2 N = 11 •Fig. 14.15 Lengthdependenceofcontractionofsmoothmuscleshowsabell-shapedresponsesimilartothatseeninskeletalmuscle.Thesmoothmusclestripswereobtainedfromhogcarotidartery.Contractionwasinducedbypotassiumdepolarization.Optimalmusclelength(Lo)wasgraphicallydeterminedasthelengthatwhichmaximaltension(Po)wasdeveloped.Redcircles,passivetension;bluecircles,activetension,triangles,totaltension;(FromHerlihyJT,MurphyRA.Circ. Res. 1973;33:275-283.) the attached force-generating configuration because of their slow cycling kinetics.