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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1210-1215.)
© 1997 American Heart Association, Inc.

Articles

Myosin Gene Expression and Cell Phenotypes in Vascular Smooth Muscle During Development, in Experimental Models, and in Vascular Disease

Saverio Sartore; Angela Chiavegato; Rafaella Franch; Elisabetta Faggin; ; Paolo Pauletto

From the Departments of Biomedical Sciences (S.S., A.C., R.F.) and of Clinical and Experimental Medicine (E.F., P.P.), University of Padua, and the CNR Unit for Muscle Biology and Physiopathology (S.S.), Padua, Italy.

Correspondence to Saverio Sartore, Department of Biomedical Sciences, University of Padua, Viale Colombo 3, I-35121 Padua, Italy. E-mail sartore{at}civ.bio.unipd.it

	Abstract

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
Abstract In the aortic wall of mammalian species, the maturation phase of smooth muscle cell (SMC) lineage is characterized by two temporally correlated but opposite regulatory processes of gene expression: upregulation of SM type SM2 myosin isoform and downregulation of brain (myosin heavy chain B)- and platelet (myosin heavy chain A_pla)-type nonmuscle myosins. Using the myosin isoform approach to study vascular SMC biology, we have shown (1) a marked SMC heterogeneity in adult arterial vessels, ie, coexistence of an "immature" and a fully differentiated SMC population; and (2) the propensity of the immature type SMC population to be activated in experimental models and human vascular diseases that are characterized by proliferation and migration of medial SMCs into the subendothelial space.

Key Words: smooth muscle cells • atherosclerosis • myosin isoforms • differentiation

	Introduction

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
Growth and differentiation of SMCs have an important impact on the biology of several diffuse vascular diseases, such as atherosclerosis and restenosis after angioplasty or vein grafting.¹ The basic feature of these pathologies is the proliferation/migration of medial SMCs to the intima, which is accompanied by marked morphological, biochemical, and functional changes of the SMCs in the adult arterial vessel.¹ Unlike skeletal muscle fibers and cardiac myocytes, SMCs display remarkable plasticity in terms of differentiation, proliferation, and motility, characteristics that are particularly evident when adult arteries are subjected to wall injuries.¹ Interestingly, all three muscle tissues recapitulate some aspects of ontogenesis when hyperplastic or hypertrophic growth is induced in adulthood as part of an adaptive response to some pathophysiological stimulus.^{1 2} Thus, delineation of the differentiation profile of vascular SMCs in experimental animal models and human disease could be instrumental for understanding the basic mechanism(s) that allows development of the atherosclerotic lesion and restenosis. Among the various SMC differentiation markers, myosin appears to be a powerful tool to study the structural modifications that these cells undergo during development, in vitro, and in vascular disease.³ In striated muscle, this protein is expressed in tissues and in a developmental stage–specific manner, and the myosin isoform pattern correlates with specific contractile properties.⁴ In SM and NM systems, recent achievements in the biochemistry of the respective myosin variants indicate that structural modifications of the heavy subunits (ie, MyHC) can be associated with different functional characteristics.⁴ In addition, it has been found that NM-MyHC isoforms are differentially expressed in SMCs during physiological and pathological vascular remodeling³ and that SM myosin is present exclusively in the SMC lineage during development.⁵ These data clearly indicate that myosin is a reliable marker to study the phenotypic SMC transitions and the factors that can affect the differentiative stability of these cells.^{1 3 4 6} We will review the work done in this field and place a major emphasis on the existence of different levels of SMC heterogeneity in developmental and pathological vascular remodeling.

	Some Structural Features of Myosin Isoforms

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
Given the coexistence of SM and NM variants of MyHC in vascular SMCs, a brief description of the biochemistry of both isoforms will be furnished. In the arterial vessels, two isoforms of SM-MyHC, SM1 (204 kD) and SM2 (200 kD), are the products of an alternative mRNA splicing process at the 3' C terminus of a primary transcript obtained from a single gene^{3 6} that has been localized to chromosome 16q12 in humans. Subvariants of SM1 and SM2, called SM1A and SM2A, respectively, are expressed predominantly in vascular SM tissue and are formed by an alternative splicing mechanism at the level of a 25/50-kD junction at the 5' N terminus.^{3 6} It seems that the lack of 7 amino acids in the "vascular" type A MyHC isoform is responsible for the lower ATPase activity and slower movement of actin filaments in in vitro motility assay with respect to the "visceral" variants (SM1B/SM2B).⁴

Two genes coding for NM-MyHC isoforms, named MyHC-A (196 kD) and MyHC-B (198/200 kD), are expressed in vascular SMCs^{6 7} and have been mapped to chromosomes 22q11.2 and 17p13, respectively. At the protein level and with techniques that use antibodies to sequence-specific peptides, there is evidence that another NM-MyHC subtype exists in the vascular wall: the MyHC-A_pla (platelet type, 200 kD).⁸ Both MyHC-A and MyHC-B show distinct intracellular localization in interphase cells and throughout mitosis. In addition, the velocity of movement of actin filaments is faster for MyHC-A than for MyHC-B.⁶

	Myosin Isoforms and SMC Heterogeneity During Development and in Adult and Aged Arteries

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
A large number of markers have been used to study the cellular pathway whereby the conversion from uncommitted mesodermal cells to fully committed SMCs is accomplished during embryogenesis (discussed in Reference 1¹ ). Among the most studied differentiation markers, SM-type -actin is the first to be expressed in the course of aortic vasculogenesis in the chicken,⁹ followed by SM22 and calponin.¹ All three proteins, however, are transiently present in embryonic cardiac and skeletal muscle, although during later development their expression is restricted to SM tissue.^{1 6} In embryonic mice, SM-MyHC expression is first detected at 10.5 days postcoitum,⁵ ie, later than the other three markers but specifically localized in SMCs. Given that SMC lineage can be divided into three stages, namely, commitment, differentiation, and maturation,¹ the appearance of SM myosin during vasculogenesis can be associated with the intermediate (differentiation) phase of this process.

The SM1 isoform is constitutively expressed throughout development in rabbit,¹⁰ human,^{11 12} and bovine¹³ aortas, whereas SM2 appears after birth in rabbit¹⁰ and bovine¹³ aortas and at a late gestational stage in human fetal arteries.^{11 12} However, SM2 expression during closure of the ductus arteriosus and umbilical arteries does not fit this scheme. In the fetal rabbit,¹⁴ closure of these vessels is preceded by the early expression of SM2, which is lacking in umbilical veins and other embryonic blood vessels. The adult human pulmonary artery is distinct from the aorta owing to the presence of an additional SM-type isoform of 190 kD (MyHC-3).¹⁵ In bovine pulmonary artery, a specific distribution of SM1/SM2 is seen in large, medium, and small segments of the vessel.¹⁶ Similarly, a marked SMC heterogeneity in the SM1/SM2 content is shown in the bovine inferior vena cava and portal vein.¹⁶ In addition, the porcine inferior vena cava contains a unique isoform of 196 kD (MyHC₃),¹⁷ possibly similar to MyHC-3. Differences in the distribution of SM1/SM2 isoforms are also evident within a given arterial vessel.

SM-MyHC composition differs in developing and adult arteries, between adult arteries and veins, and within the same vessel as well. The MyHC-B NM myosin isoform (also identified as SMemb^{11 18} ) present in aortic SM is downregulated with development,^{11 18} in close relationship with the upregulation of SM2. In humans, however, MyHC-B is detected in the adult also.¹¹

Using a panel of monoclonal antibodies to platelet MyHC whose specific epitope is localized to the 15-kD -chymotryptic fragment of the head portion of the myosin molecule,¹⁹ we have been able to demonstrate a time-dependent regulation of 196-kD MyHC-A_pla isoform expression in the human aorta¹² that is similar to that of MyHC-B.¹¹ By contrast, another 196-kD MyHC-A_pla isoform is constitutively expressed throughout all developmental stages examined.¹² This latter isoform shows a distribution of immunostaining pattern in various NM tissues/cells that is similar to that of MyHC-A– (MyHC-A–like).¹²

The use of anti–MyHC-A_pla antibodies in the study of differentiation/maturation of rabbit aortic SMCs has revealed that a 200-kD NM-MyHC is expressed from day 19 in utero until birth (SMC positive with NM-F6 antibody, tentatively named MyHC-A_pla1), whereas another isoform of 200 kD is present in the postnatal period of development but its expression declines progressively up to day 90 (tentatively named MyHC-A_pla2).²⁰ Time-dependent downregulation of postnatal-type SMCs is more rapid in the carotid artery versus the aorta.²¹ In the adult, this phenotype is still expressed in a minority of aortic SMCs, accounting for 4% of the total SMC number²² at the level of aortic valve and 10% at the level of the aortic bifurcation.²³

On this basis, we have identified a three-step maturation process: fetal (SM1+MyHC-A_pla1/2), postnatal (SM1/SM2+MyHC-A_pla2), and adult (SM1/SM2; see also Fig 1).^{3 20} Thus, in the adult rabbit aorta, two developmentally regulated SMC populations appear during the course of the maturation phase of the SMC lineage program. Extensive SMC heterogeneity and persistence of "immature" medial SMC populations result from the differential distribution of NM-MyHC_pla myosins¹³ and the peculiar SM1/SM2-metavinculin composition of morphologically distinct SMC populations.²⁴

View larger version (45K): [in this window] [in a new window]   Figure 1. Schematic representation of phenotypic changes occurring during developmental and pathological remodeling in experimental animals and humans. Three developmental stages can be identified in the course of differentiation/maturation of the rabbit aorta, as characterized by expression of fetal- (red), postnatal- (blue), and adult- (green) type SMCs. Small arteries do not undergo such cell transition but express the fetal-type myosin isoform repertoire of the aorta in both fetal and adult stages of development. A minority of vessels, especially evident in fetal or young animals, do not possess SM myosin (yellow). During later development, the majority of microvessels display a fetal-type SMC content. Application of a number of exogenous stimuli to adult rabbit aortas induces expansion (upregulation) or reduction (downregulation) of postnatal-type medial SMCs. The former event may be eventually accompanied by proliferation/migration of this cell population into the subendothelial space and the subsequent formation of an intimal thickening/atherosclerotic lesion. In human coronary arteries, the phenotypic status of SMCs in the atheroma might be involved in dictating the tendency to restenosis after balloon angioplasty. Nothing is known, however, about the differentiation pattern of medial SMCs subjacent to restenotic tissue.

SMC heterogeneity is less evident in the microvasculature, where the cell transitions described for large vessels are lacking. In peripheral resistance arterioles, SM and NM-MyHC_pla myosins are coexpressed. Depending on localization (skeletal muscle²³ or dental pulp²¹ ), a variable number of these small vessels do not express SM myosin, as reported by Price et al²⁵ (see also Fig 1). Vessels lacking SM myosin are more numerous in the postnatal period than in the adult.^{21 25}

In rats, the basic SM1/SM2 isoform expression does not vary with aging (13 or 28 months), but there is downregulation of the MyHC-A_pla2 isoform 12 days after birth.²⁶ The MyHC-A_pla1 isoform is undetectable in this system.²⁶

	SM Myosin Expression in Cultured Vascular SMCs

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
It is well known that SMCs grown in vitro can undergo a phenotypic cell transition from the normally quiescent ("contractile") status observed in vivo to a proliferative-secretory state²⁷ that resembles the SMC phenotypic change in atherogenesis and vasculogenesis.¹ The general feature of cultured SMCs is the downregulation of SM myosin isoform expression, particularly of SM2,¹³ concomitant with upregulation of NM myosin variants MyHC-A_pla1, MyHC-A, and MyHC-B.⁴ These tendencies depend, however, on cellular density, serum concentration, and substrate for attachment.²⁷ Upregulation of SM1/SM2 and downregulation of both MyHC-A and MyHC-B expression can be seen in rat cultured SMCs that have been subjected to mechanical strain under culture conditions that favor SMC proliferation.²⁸ This finding indicates that growth and differentiation are not mutually exclusive and that differentiation potential is retained in vitro, provided permissive conditions are applied to the culture.²⁸

	Environmental Cues Affecting Myosin Isoform Expression and SMC Heterogeneity

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
Myosin gene expression can be regulated during early development (effect on the differentiation phase of the SMC lineage program) or in adulthood (alteration of the stability of the fully differentiated SMC phenotype). Retinoic acid is involved in the precocious upregulation of SM2 in the ductus arteriosus, as demonstrated by the use of transgenic mice carrying a retinoic acid–responsive element.²⁹ There are a number of experimental conditions under which expression of MyHC-A_pla-type NM myosin isoforms can be affected. As shown in Fig 1 and reviewed in Reference 3³ , there are various chemical and hormonal stimuli or pathophysiological conditions that can increase the "size" of the fetal/postnatal SMC compartment in the arterial media. This may eventually be accompanied by loss of positional control, directional movement from the media to the intima, and accumulation in the subendothelial space or preexisting intimal layer. Conversely, the decrease or disappearance of postnatal SMCs from the media is never associated with neointima formation. As previously pointed out,³ expansion of fetal/postnatal SMC populations seems to be a prerequisite for neointima formation. This change in medial SMCs is probably necessary to acquire the competence for migration or proliferation, although proliferation and differentiation are not necessarily linked to each other.²

	SMC Populations and Myosin Isoform Expression in Atherogenesis, Endothelial Lesions, and Restenosis

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
SMCs play a fundamental role in the pathogenesis of atherosclerosis.³ We were the first to demonstrate that in experimentally induced atherosclerotic lesions (of endogenous or exogenous origin), reexpression of an immature type of myosin isoform pattern (SM1+MyHC-A_pla2) occurs.^{30 31} Other authors have also shown that a fetal-like MyHC-B expression is similarly upregulated in the rabbit plaque.¹⁸ In this latter work, MyHC-B expression in SMCs was restricted to the atherosclerotic lesion, whereas MyHC-A_pla2 was also upregulated in the medial region subjacent the plaque.^{30 31} The lack of SM2 expression and upregulation of MyHC-B are also hallmarks of human atherosclerosis.¹¹

The importance of immature-type SMC populations as the cellular target of some risk factors is supported by the following observations: (1) Atherosclerotic lesions in hypercholesterolemic rabbits develop exclusively in arterial sites that, in normocholesterolemic animals, contain clusters of postnatal-type SMCs,^{21 31} and (2) the atherosclerosis resistance of some species (eg, rat) when exposed to a cholesterol enriched-diet²⁶ or endogenous hyperlipidemia associated with NO synthase inhibition is accompanied by the lack of expansion of immature-type SMC populations.³²

A high serum cholesterol level is a favorable condition for atherogenesis and hence for the expansion of immature-type SMC populations. However, a high serum cholesterol level can be maintained even with the use of the dihydropyridine Ca²⁺ channel blockers nifedipine³³ and nitrendipine³⁴ that act selectively as antiatherosclerotic drugs by reducing the development of plaque via lowering the number of immature-type SMCs.

The formation of a thickened intima after balloon angioplasty in the rabbit aorta/carotid artery has furnished useful information by serving as a model for revealing the relationship between changes in the differentiation profile and the proliferative behavior of SMCs. For example, SM1 and MyHC-B, but not SM2, are expressed in the neointima, again demonstrating the presence of an "embryonic phenotype."³⁵ Proliferating medial SMCs that underlie the thickened intima appear to specifically contain MyHC-B.³⁵ Similar results were obtained with our monoclonal antibodies specific for MyHC-A_pla isoforms (Fig 2). A fetal-type SMC phenotype was expressed in the neointima (also confirmed by the presence of the EIIIA fibronectin variant³⁶ ), whereas a postnatal-type SMC population was visible in the subjacent media. Most of the proliferating SMCs in media and all of those in the neointima were of the immature type, although only a minority of immature SMCs were actively proliferating. On the other hand, the majority of this cell population is not involved in apoptosis. These findings show again that (1) growth and differentiation are two distinct phenomena in the SM system and (2) acquisition of the immature SMC phenotype does not make this cell particularly vulnerable to apoptosis, at least at this time of the process.

View larger version (129K): [in this window] [in a new window]   Figure 2. Photomicrographs showing immunofluorescence patterns of injured rabbit carotid 7 days after angioplasty (A-D, I-L) and of the contralateral intact carotid artery (E-H) with anti-myosin (A-C, E-G, I, K), IST9 anti-EIIIA fibronectin (D, H), and anti-BrdU (J) antibodies. A, E: SM-E7 anti-SM myosin (specific for SM1/SM2); B, F, I, K: NM-G2 anti-NM myosin (specific for MyHC-Apla2); and C, G: NM-F6 anti-NM myosin (specific for MyHC-Apla1). TUNEL-positive nuclei are shown in panel L. a indicates adventitia; e, endothelium; iel, internal elastic lamina; it, intimal thickening; and m, tunica media. Note that medial SMCs in the control vessel are of the adult type except for rare, postnatal-type SMCs (F). In the neointima and underlying media, SMCs are brightly stained with NM-G2 and weakly with SM-E7, whereas NM-F6 and anti-fibronectin antibodies label the intimal thickening almost exclusively. A few NM-F6–positive cells can be detected just beneath the internal elastic lamina (double asterisk in C). Thus, postnatal and fetal SMCs are present in the media and neointima, respectively, of the injured carotid artery. BrdU-positive cells are localized mainly in the inner part of the carotid artery, where postnatal SMCs and a few apoptotic cells are also visible. Note that the majority of postnatal SMCs (I) contain BrdU-positive nuclei (stars), but some proliferating cells are unreactive to NM-G2 (asterisks in I and J). Similarly, apoptotic cells in K can stain positively (asterisks in L) or negatively (star) for NM-G2 with this antibody. BrdU injections in rabbit were performed as previously described.3 Angioplasty was carried out by essentially following the procedure described in Reference 36. A-D, E-F, and I-J are serial cryosections. K, L are double-immunofluorescence images obtained with rhodaminated anti–NM-G2 and fluoresceinated antibody contained in Boehringer Mannheim's TUNEL kit. Bar=60 µm.

Alteration in the stability of the SMC differentiation pattern also occurs in restenosis after directional atherectomy. Data collected by Isner and coworkers³⁷ in human coronary arteries indicated the expression of MyHC-B was upregulated compared with that in one of the primary lesions (atherosclerotic plaque) from the same arterial site of the same patient. MyHC-A expression in primary versus secondary lesions does not vary.³⁷ A prospective study performed on patients who underwent directional atherectomy revealed that the MyHC-B mRNA content of the primary lesion was predictive of the tendency to develop restenosis.³⁷ In other words, in coronary arteries with numerous immature SMCs in the plaque, there is a higher tendency to restenosis.

The existence of immature-type SMCs in the intimal thickening (ie, the "soil"² ) that precedes the atherosclerotic lesion¹² should also be taken into account. The possible site specificity of the distribution of such cell populations¹² might influence the final outcome of SMC composition in the plaque and, hence, that of the restenosis process. Although a high proliferating-cell nuclear antigen level and high outgrowth from tissue explants are displayed by restenotic compared with primary lesion specimens,³⁷ a study aimed at correlating such indices to the tendency of retrieving the immature-type pattern of MyHC isoforms has not yet been carried out. This point is especially important if one considers that the replicating level of coronary SMCs is still disputed.²

	Experimental Hypertension, Changes in Myosin Isoform Pattern, and SMC Heterogeneity in Large Conduit Arteries and Peripheral Vessels

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
In a rabbit model of renovascular hypertension characterized by intimal thickening, aortic wall hypertrophy was accompanied by marked augmentation of the postnatal-type SMC population in the media.³⁸ Similarly, in stroke-prone spontaneously hypertensive rats, the increase in blood pressure leads to SMC hypertrophy, as mirrored by expansion of the immature SMC population.³⁹ Thus, proliferation/migration and hypertrophy of medial SMCs are both characterized by the same phenotypic change. Blood pressure level is not involved in regulating such phenomena, as demonstrated by the preventive effect of anipamil, a phenylalkylamine-derived Ca²⁺ antagonist, on intimal thickening formation in renovascular hypertensive rabbits.⁴⁰ The pharmacological effect of this drug is accomplished not only by reducing in vitro expression of MyHC-A_pla2 (an effect also elicited by the dihydropyridine Ca²⁺ channel blockers) but also by maintaining adequate levels of SM myosin isoform expression.

Whereas in large vessels, such as the rabbit aorta, the postnatal-type SMC population is susceptible to variation in size (see Fig 1), the SMC population in resistance small vessels is stable and does not change, even when an increase in blood pressure is applied.²³ This is another demonstration that the biology of SMCs in these two arterial regions is intrinsically different. Unfortunately, data about the differentiation profile of SMCs and the remodeling process of human arterioles in hypertensive patients are still lacking.

	Perspectives

Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 
The data discussed in this review point to the existence of SMC heterogeneity in vascular tissue on the basis of the structural and functional diversity of unique cell types. Identification of a peculiar SMC population that is involved in the "response-to-injury" process supports the hypothesis that a specific cellular "soil" might be an advantageous condition for development of the arterial wall lesion. The following issues should be examined in future work:

(1) A detailed, in vivo distribution map of basic SMC phenotypic characteristics in arteries versus veins and in arteries of different size versus those of the periphery is necessary to acquire sufficient information about the biology of vascular SMCs. Despite widespread use of vein tissue in bypass surgery, the biology of venous SMCs is poorly understood. The use, at protein and nucleic acid levels, of myosin isoform markers seems particularly useful to monitor changes in the late phase of development.

(2) Because in the adult the hyperplastic/hypertrophic growth response of the arterial wall to injury includes some recapitulation of ontogenesis, the early phases of vasculogenesis/angiogenesis should be established in more detail. The use of myosin isoform probes in association with other differentiation markers (eg, SM-type -actin, SM22, and calponin) seems to be particularly promising.

(3) The existence of structural and functional SMC heterogeneity in arterial vessels has also been confirmed by cell cloning in the rat.^{41 42} Some SMC populations that have originated from cloning of adult SM tissue display features in common with developing and "phenotype-modulated" adult rat SMCs.^{41 42} The proliferative/migratory/differentiative capacity of cell clones should be tested with different myosin isoform contents to ascertain the correspondence with the in vivo behavior of injured SMCs.

(4) With the consideration that NM myosin isoform expression is particularly evident at some "strategic" sites of adult arteries, it would be of interest to study whether such distribution is due to a selective availability of environmental cues or is dictated by a morphogenic process initiated early during vasculogenesis and completed after birth.

	Selected Abbreviations and Acronyms

 

MyHC = myosin heavy chain NM = nonmuscle SM(C) = smooth muscle (cell) TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling

	Acknowledgments

 
This work was supported in part by the Biomedical Association for Vascular Research. The authors thank Lisa Galliani for her excellent editing work.

Received March 4, 1997; accepted March 7, 1997.

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Top Abstract Introduction Some Structural Features of... Myosin Isoforms and SMC... SM Myosin Expression in... Environmental Cues Affecting... SMC Populations and Myosin... Experimental Hypertension,... Perspectives References

 

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