Experimental Biology and Medicine 230:829-835 (2005)
© 2005 Society for Experimental Biology and Medicine
MINIREVIEW
Molecular Aspects of Arterial Smooth Muscle Contraction: Focus on Rho
Rob H. P. Hilgers and
R. Clinton Webb1
Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912
1To whom requests for reprints should be addressed at Department of Physiology, 1120 15th Street, Medical College of Georgia, Augusta, GA 30912-3000. E-mail: cwebb{at}mail.mcg.edu
 |
Abstract
|
|---|
The vascular smooth muscle cell is a highly specialized cell whose primary function is contraction and relaxation. It expresses a variety of contractile proteins, ion channels, and signalling molecules that regulate contraction. Upon contraction, vascular smooth muscle cells shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. Contractile activity in vascular smooth muscle cells is initiated by a Ca2+-calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca2+-sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase, thereby maintaining force. Removal of Ca2+ from the cytosol and stimulation of myoson phosphatase initiate the relaxation of vascular smooth muscle.
Key Words: smooth muscle • contraction • vascular • calcium • signaling
|
Introduction
|
|---|
Smooth muscle cells constitute the walls of various organs and tubes of the body including blood vessels, stomach, intestines, bladder, airways, uterus, and the penile and clitoral cavernosal sinuses. Smooth muscle derives its name from the fact that it lacks the striated banding pattern that is characteristic of cardiac and skeletal muscle. Smooth muscle cells receive neural innervation from the autonomic nervous system. In addition, the contractile state of smooth muscle is controlled by several hormonal and autocrine/paracrine actions. Smooth muscle cells also develop tonic and phasic contractions in response to changes in load or length. Regardless of the stimulus, smooth muscle cells use cross-bridge cycling (between actin and myosin) to develop force and calcium ions (Ca2+) that initiate the underlying molecular signaling that leads to contraction.
The vascular smooth muscle cell is a highly specialized cell whose principal function is contraction. It expresses a variety of contractile proteins, ion channels, and signaling molecules that regulate contraction. On contraction, vascular smooth muscle cells shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. However, this contractile phenotype can differentiate into a synthetic phenotype during, for instance, vasculogenesis, which is characterized by proliferation and production of extracellular matrix components of the arterial wall (1). In this minireview, we focus primarily on the contractile phenotype of vascular smooth muscle cells and describe the molecular-signaling pathways involved in regulating contraction. For a more in-depth outline of the molecular mechanism of smooth muscle contraction and its regulation, the reader is referred to several recently published reviews (2–6).
|
The Contractile Mechanism
|
|---|
In the intact body, the process of smooth muscle contraction is principally regulated by pharmacomechanic activation (i.e., activation by ligands of cell surface receptors) and electromechanic activation (i.e., stretch, intraluminal pressure) of the contractile proteins myosin and actin (7). In the latter, a depolarization of the membrane’s resting potential, brought on by the firing of action potentials or by activation of stretch-dependent ion channels and voltage-operated Ca2+ channels in the plasma membrane, triggers the influx of Ca2+ and ultimately leads to contraction. Myogenic tone or pressure-induced constriction of arterioles and small-resistance arteries depends on this electromechanic coupling (8, 9). For contraction to occur, myosin light chain (MLC) kinase, activated by Ca2+ calmodulin, must phosphorylate Ser 19 of the 20-kDa regulatory MLC, enabling the molecular interaction of myosin with actin (10, 11). Energy released from ATP by myosin ATPase activity results in the cycling of the myosin cross-bridges with actin for contraction (12, 13). Thus, contractile activity in smooth muscle cells is primarily determined by the phosphorylation state of the MLC. In some smooth muscle cells, the phosphorylation of the MLC is maintained at a low level in the absence of external stimuli (i.e., no receptor or mechanical activation; Ref. 14). This activity results in what is known as smooth muscle tone, and its intensity can be varied.
|
Ca2+-Dependent Contraction of Smooth Muscle
|
|---|
Contraction of smooth muscle is initiated by a Ca2+-mediated change in the thick (myosin) filaments, whereas in striated muscle, Ca2+ mediates contraction by changes in the thin (actin) filaments. In response to specific stimuli in smooth muscle, the 
1-adrenoceptor agonist norepinephrine released from the sympathetic nerves within the arterial wall for instance, the intracellular concentration of Ca2+ rapidly increases and declines to a level that is elevated above basal in the continued presence of the agonist (15). This initial transient increase in cytosolic Ca2+ arises from Ca2+ released from intracellular stores (sarcoplasmic reticulum), while the latter increase arises from entry from the extracellular space through Ca2+ channels (receptor-operated Ca2+ channels), as shown by high-resolution confocal imaging (see Ref. 5 for a comprehensive review). The biochemical signals that trigger this Ca2+ release are documented in detail (see Refs. 16 and 17 for reviews) and will be described here only briefly. Phospholipase C (PLC) is activated by the heterotrimeric G protein G,q on binding of agonists such as norepinephrine, angiotensin II, or endothelin-1 to serpentine receptors on the smooth muscle membrane (Fig. 1
). PLC is specific for the membrane lipid phosphatidylinositol 4,5-biphosphate to catalyze the formation of two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The binding of IP3 to receptors on the sarcoplasmic reticulum results in the release of Ca2+ into the cytosol. The primary target protein of this initial rise in intracellular Ca2+ is believed to be calmodulin, a member of the family of EF hand Ca2+-binding proteins (18). The binding of Ca2+ to these four EF hands causes a conformational change in the calmodulin molecule, allowing a subsequent interaction with MLC kinase. This association results in a conformational change of the calmodulin-MLC kinase complex, exposing the catalytic site. This sequence of events leads to the activation of MLC kinase and the phosphorylation of Ser 19 of the 20-kDa regulatory MLC (MLC20; Refs. 10, 11). The second messenger, DAG, which is released on agonist-induced and/or stretch-induced PLC activation, activates protein kinase C (PKC), which phosphorylates specific target proteins. There are several isozymes of PKC in smooth muscle such as PKC and ß (those that are DAG dependent and Ca2+ dependent) or PKC
(which requires only DAG), and each has a tissue-specific role (e.g., vascular, uterine, intestinal). In many cases, PKC has contraction-promoting effects such as phosphorylation of many kinases including MLC kinase, ERK1/2, Rho-kinase (p160ROCK), and calmodulin-dependent protein kinase II, as well as various ion channels and ion transporters. Phorbol esters, a group of synthetic compounds known to activate PKC, mimic the action of DAG and cause contraction of smooth muscle.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 1. Molecular signaling pathways involved in agonist-induced smooth muscle cell contraction. The contractile response is initiated by a rapid and transient rise in intracellular Ca2+, followed by a Ca2+-calmodulin interaction to stimulate phosphorylation of the MLC. Refer to the text for a more detailed outline.
|
|
Finally, L-type Ca2+ channels (i.e., voltage-operated Ca2+ channels) in the membrane also open in response to the membrane depolarization brought on by stretch of the smooth muscle cell, which is supposed to play an important role in myogenic reactivity and tone (19–21).
|
Ca2+-Sensitization Mechanism and Contraction of Smooth Muscle
|
|---|
Contractility of vascular smooth muscle is not only regulated by intracellular Ca2+, but also by Ca2+-independent mechanisms. In addition to the Ca2+-dependent activation of MLC kinase, the state of MLC phosphorylation is further regulated by MLC phosphatase, which is also known as myosin phosphatase (16, 22, 23) and removes the high-energy phosphate from the MLC to promote smooth muscle relaxation (Fig. 2). There are three subunits of MLC phosphatase: a 37-kDa catalytic subunit (PP1c), a small noncatalytic subunit of unknown function (24), and a 110-kDa to 130-kDa myosin-binding subunit (MYPT1). The binding of MYPT1 to PP1c inhibits the enzymatic activity of MLC phosphatase, allowing the MLC to remain phosphorylated and, thereby, promoting contraction (25). Experiments have shown that activated G-proteins are involved in the signaling pathway for this Ca2+ sensitization because GTP
S, a nonhydrolyzable GTP analog, increases MLC phosphorylation and potentiates contraction. GTPS was also demonstrated to decrease the rate of MLC dephosphorylation, which is consistent with an overall decrease in MLC phosphatase activity (26). Subsequent experiments have shown that the small G protein RhoA and its downstream target Rho kinase play an important role in the regulation of MLC phosphatase activity (27). RhoA is a monomeric G-protein that can be activated by several agonists including angiotensin II (28). Its activity is regulated by the binding of GTP, a transition facilitated by Rho-guanine nucleotide exchange factors (Rho-GEFs) that enable the exchange of nucleotide to activate RhoA-GDP to RhoA-GTP (29). This activated RhoA-GTP binds to and activates Rho kinase, a serine/threonine kinase (30), which subsequently phosphorylates the myosin-binding subunit of MLC phosphatase (MYPT1) and inhibits its activity (31) and, thus, promotes the phosphorylated state of the MLC (Fig. 2). A translocation of Rho kinase and RhoA to the cell membrane has been shown to occur on agonist activation (16, 32); however; how Rho kinase might regulate the dephosphorylation of myosin in the core of the cell is unknown. It might involve dissociation of MYPT1 and PP1c on the membrane, thereby decreasing MLC phosphatase activity (33). Pharmacologic inhibitors of Rho kinase, such as fasudil, Y-27632, and HA-1077, block its activity by competing with the ATP-binding site on the enzyme (34–36). Rho kinase inhibition induces the relaxation of isolated segments of smooth muscle that are contracted by a variety of agonists (37, 38). In the intact animal, the pharmacologic inhibitors of Rho kinase have been shown to cause relaxation of smooth muscle in arteries, resulting in a blood pressure–lowering effect (27, 39).
View larger version (31K):
[in this window]
[in a new window]
|
Figure 2. Ca2+-sensitization mechanism and contraction of smooth muscle. Contractility of smooth muscle can also be regulated by Ca2+-independent mechanisms involving G-protein–coupled receptor binding. When agonists bind to serpentine receptors on the outer membrane of the smooth muscle, the Rho-GTP is activated by Rho-guanine nucleotide exchange factors. This activated RhoA-GTP binds to and activates Rho kinase, which subsequently phosphorylates the myosin-binding subunit of MLC phosphatase and inhibits its activity, thus promoting the phosphorylated state of MLC that leads to contraction.
|
|
Several recent studies suggest a role for additional regulators of MLC kinase and phosphatase (16, 23, 40). The small protein CPI-17, once phosphorylated, is able to bind to the catalytic subunit of MLC phosphatase (PP1c) to inhibit the enzyme’s activity (41, 42). CPI-17 is expressed in mammalian vascular smooth muscle (43, 44), which also serves as a substrate for both Rho-kinase and PKC (44). Thus, Ca2+ sensitization may involve Rho-kinase–mediated and/or PKC-mediated phosphorylation of CPI-17 to increase MLC20 phosphorylation and prolong smooth muscle contraction (Fig. 3).
View larger version (20K):
[in this window]
[in a new window]
|
Figure 3. Additional regulators of MLC kinase and phosphatase. Phosphorylated CPI-17 is able to bind to the catalytic subunit of myosin phosphatase to inhibit the enzyme’s activity, resulting in prolonged smooth muscle contraction. Both Rho-kinase and protein kinase C can activate CPI-17. Furthermore, calmodulin-dependent protein kinase II promotes smooth muscle cell relaxation by decreasing the sensitivity of MLC kinase for Ca2+. The small protein telokin mediates Ca2+ desensitization through activation of myosin phosphatase, leading to a decrease in MLC phosphorylation and, therefore, promoting smooth muscle cell relaxation.
|
|
Calmodulin-dependent protein kinase II promotes smooth muscle relaxation by decreasing the sensitivity of MLC kinase for Ca2+. Additionally, the 17-kDa protein telokin mediates Ca2+ desensitization through activation of myosin phosphatase in smooth muscle cells, which leads to a decreased MLC phosphorylation and smooth muscle contraction (45, 46; Fig. 3
).
An important question facing the smooth muscle physiologist is: what is the link between receptor occupation and activation of the Ca2+-sensitizing activity of the RhoA/Rho kinase-signaling cascade? Currently, it is thought that receptors activate a heterotrimeric G protein that is coupled to RhoA/Rho kinase signaling via RhoGEFs. Because RhoGEFs facilitate the activation of RhoA, they regulate the duration and intensity of signaling via heterotrimeric G protein–receptor coupling. There are approximately 70 RhoGEFs in the human genome (47) and three RhoGEFs have been identified in smooth muscle: PDZ-RhoGEF, LARG (leukemia-associated RhoGEF), and p115-RhoGEF. Increased expression and/or activity of RhoGEF proteins could augment contractile activation of smooth muscle and, therefore, play a role in diseases such as hypertension and asthma, where an augmented response contributes to the pathophysiology. Recent observations from our laboratory showed an involvement of reactive oxygen species in Ca2+ sensitization by activation of RhoA and a subsequent increase in Rho kinase activity, providing a direct link between reactive oxygen species and the RhoA/Rho kinase signaling pathway in the pathogenesis of hypertension (48).
|
Other Mechanisms of Smooth Muscle Cell Contraction
|
|---|
It has been proposed that actin filament rearrangement or remodeling may play a role in smooth muscle cell contraction (49, 50). The hypothesis assumes that actin-myosin interactions cause the initial development of force and a "gluing" of actin filaments to attachment sites where they assemble in dense bodies to form a cytoskeletal scaffold that maintains tension in the absence of further cross-bridge cycling. Indeed, disruption of actin filaments has been associated with reduced agonist-induced Ca2+ signaling (51). Caldesmon and calponin are actin-associated proteins that have been shown to inhibit actomysin ATPase activity (52, 53). Caldesmon has proven capable of regulating force in smooth muscle (52). Furthermore, the inhibitory effect of caldesmon on the actomysin ATPase activity can be reversed by phosphorylation, indicating a regulation mechanism of its inhibitory action (54). Others have shown that both extracellular signal-related kinase (ERK) MAP kinase and p38 MAP kinase are activated during agonist-induced smooth muscle stimulation. The activation of ERK MAP kinase leads to the phosphorylation of caldesmon (55), while p38 MAP kinase increases the phosphorylation and activation of heat-shock protein 27 (HSP27; Ref. 56). Interestingly, HSP27 is a known regulator of actin polymerization (57), suggesting that actin rearrangement is an important event in the mechanism of force maintenance during smooth muscle contraction.
Other cytoskeletal proteins such as microtubules have been demonstrated to play a role in vascular smooth muscle contraction. Microtubule depolymerization was shown to enhance agonist-induced contraction of isolated aortic rings (58) and increased myogenic tone in isolated cremaster arterioles (59). Our group found that Rho-kinase activation facilitated this enhanced contraction (60, 61). Overall, these data indicate that cytoskeletal rearrangement is crucial during prolonged smooth muscle contraction and that these events might play an important role in arterial remodeling during vascular pathologies, such as hypertension.
|
Concluding Remarks
|
|---|
Layers of smooth muscle cells line the walls of various organs and tubes, and the contractile function of smooth muscle is under voluntary control. The contractile response is initiated by a rapid and transient increase in intracellular Ca2+ followed by a Ca2+-calmodulin interaction to stimulate phosphorylation of the MLC. To enable force maintenance, a Ca2+ sensitization of the contractile proteins is signaled by the RhoA/Rho kinase pathway, in concert with other proteins like CPI-17, to inhibit the dephosphorylation of the MLC phosphatase. Understandably, removal of Ca2+ from the cytosol and stimulation of myosin phosphatase initiates the process of smooth muscle relaxation.
Alterations in the regulatory processes maintaining intracellular Ca2+ and MLC phosphorylation have been proposed as possible sites that contribute to the abnormal contractile events in smooth muscle cells of various organs and tissues. Increases in the activity of RhoA/Rho kinase signaling lead to increased contractile responses that may contribute to erectile dysfunction (62) in the penis and clitoris. Increased activity of the RhoA/Rho kinase signaling pathway may also contribute to augmented contraction or spastic behavior of smooth muscle in diseases such as hypertension, asthma, or atherosclerosis (27, 39, 63–66).
|
Footnotes
|
|---|
This research was funded by the National Institutes of Health (HL-74167 and HL-71138).
|
References
|
|---|
- Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 75:487–517; 1995.[Abstract/Free Full Text]
- Woodrum DA, Brophy CM. The paradox of smooth muscle physiology. Mol Cell Endocrinol 177:135–143; 2001.[Medline]
- Ito M, Nakano T, Erdodi F, Hartshorne D. Myosin phosphatase: structure, regulation and function. Mol Cell Biochem 259:197–209; 2004.[Medline]
- Meiss R. Mechanisms of smooth muscle contraction. In: Kao CY, Carsten ME, Eds. Cellular Aspects of Smooth Muscle Function. New York: Cambridge University Press, pp169–201, 1997.
- Wier W, Morgan K. Alpha1-adrenergic signaling mechanisms in contraction of resistance arteries. Rev Physiol Biochem Pharmacol 150:91–139; 2003.[Medline]
- Ogut O, Brozovich FV. Regulation of force in vascular smooth muscle. J Mol Cell Cardiol 35:347–355; 2003.[Medline]
- Somlyo A, Somlyo A. Intracellular signaling in vascular smooth muscle. Adv Exp Med Biol 346:31–38; 1993.[Medline]
- Davis MJ, Wu X, Nurkiewicz TR, Kawasaki J, Davis GE, Hill MA, Meininger GA. Integrins and mechanotransduction of the vascular myogenic response. Am J Physiol Heart Circ Physiol 280:H1427–H1433; 2001.[Abstract/Free Full Text]
- Hill MA, Zou H, Potocnik SJ, Meininger GA, Davis MJ. Signal transduction in smooth muscle: arteriolar smooth muscle mechano-transduction: Ca2+ signaling pathways underlying myogenic reactivity (invited review). J Appl Physiol 91:973–983; 2001.[Abstract/Free Full Text]
- Adelstein R, Conti M. Phosphorylation of platelet myosin increases actin-activated myosin ATPase activity. Nature 256:597–598; 1975.[Medline]
- Gallagher P, Herring B, Stull J. Myosin light chain kinases. J Muscle Res Cell Motil 18:1–16; 1997.[Medline]
- Kamm K, Stull J. The function of myosin and myosin light chain kinase phosphorylation in smooth muscle. Annu Rev Pharmacol Toxicol 25:593–620; 1985.[Medline]
- Hai C, Murphy R. Ca2+, crossbridge phosphorylation, and contraction. Annu Rev Physiol 51:285–298; 1989.[Medline]
- Barany M, Barany K. Protein phosphorylation during contraction and relaxation. In: Barany M, Ed. Biochemistry of Smooth Muscle Contraction. San Diego: Academic Press, Inc, pp321–339, 1996.
- Kasai Y, Yamazawa T, Sakurai T, Taketani Y, Iino M. Endothelium-dependent frequency modulation of Ca2+ signalling in individual vascular smooth muscle cells of the rat. J Physiol 504:349–357; 1997.[Medline]
- Somlyo AP, Somlyo AV. Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522:177–185; 2000.[Abstract/Free Full Text]
- Zhong H, Minneman K. Alpha1-adrenoceptor subtypes. Eur J Pharmacol 375:261–276; 1999.[Medline]
- Bhattacharya S, Bunick CG, Chazin WJ. Target selectivity in EF-hand calcium binding proteins. Biochim Biophys Acta 1742:69–79; 2004.[Medline]
- Tanaka Y, Hata S, Ishiro H, Ishii K, Nakayama K. Stretching releases Ca2+ from intracellular storage sites in canine cerebral arteries. Can J Physiol Pharmacol 72:19–24; 1994.[Medline]
- Davis MJ, Hill MA. Signaling Mechanisms Underlying the Vascular Myogenic Response. Physiol Rev 79:387–423, 1999.[Abstract/Free Full Text]
- Moosmang S, Schulla V, Welling A, Feil R, Feil S, Wegener JW, Hofmann F, Klugbauer N. Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation. EMBO J 22:6027–6034; 2003.[Medline]
- Fukata Y, Kaibuchi K, Amano M, Kaibuchi K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 22:32–39; 2001.[Medline]
- Solaro RJ. Myosin light chain phosphatase: a Cinderella of cellular signaling. Circ Res 87:173–175; 2000.[Free Full Text]
- Hartshorne D, Ito M, Erdodi F. Myosin light chain phosphatase: subunit composition, interactions and regulation. J Muscle Res Cell Motil 19:325–341; 1998.[Medline]
- Ichikawa K, Hirano K, Ito M, Tanaka J, Nakano T, Hartshorne D. Interactions and properties of smooth muscle myosin phosphatase. Biochemistry 35:6313–6320; 1996.[Medline]
- Kitazawa T, Masuo M, Somlyo A. G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc Natl Acad Sci U S A 88:9307–9310; 1991.[Abstract/Free Full Text]
- Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389:990–994; 1997.[Medline]
- Jackson E, Andresen B, Seasholtz T, Zhu C, Romero G. Enhanced activation of RhoA by angiotensin II in SHR preglomerular micro-vascular smooth muscle cells. J Cardiovasc Pharmacol 45:283–285; 2005.[Medline]
- Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 16:1587–1609; 2002.[Free Full Text]
- Leung T, Manser E, Tan L, Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem 270:29051–29054; 1995.[Abstract/Free Full Text]
- Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273:245–248; 1996.[Abstract]
- Taggart MJ, Lee Y-H, Morgan KG. Cellular redistribution of PKC, rhoA, and ROK following smooth muscle agonist stimulation. Exp Cell Res 251:92–101; 1999.[Medline]
- Shin H-M, Je H-D, Gallant C, Tao TC, Hartshorne DJ, Ito M, Morgan KG. Differential association and localization of myosin phosphatase subunits during agonist-induced signal transduction in smooth muscle. Circ Res 90:546–553; 2002.[Abstract/Free Full Text]
- Shimomura E, Shiraishi M, Iwanaga T, Seto M, Sasaki Y, Ikeda M, Ito K. Inhibition of protein kinase C-mediated contraction by Rho kinase inhibitor fasudil in rabbit aorta. Naunyn Schmiedebergs Arch Pharmacol 370:414–422; 2004.[Medline]
- Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y. Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. Am J Physiol Cell Physiol 278:C57–C65; 2000.[Abstract/Free Full Text]
- Breitenlechner C, Gassel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D. Protein kinase A in complex with Rho-kinase inhibitors Y-27632, fasudil, and H-1152P: structural basis of selectivity. Structure 11:1595–1607; 2003.[Medline]
- Ark M, Ozveren E, Yazici G, Korkmaz B, Buyukafsar K, Arikan O, Kubat H, Songu-Mize E. Effects of HA-1077 and Y-27632, two Rho-kinase inhibitors, in the human umbilical artery. Cell Biochem Biophys 41:331–342; 2004.[Medline]
- Chitaley K, Webb RC. Nitric oxide induces dilation of rat aorta via inhibition of Rho-kinase signaling. Hypertension 39:438–442; 2002.[Abstract/Free Full Text]
- Chitaley K, Weber D, Webb R. RhoA/Rho-kinase, vascular changes, and hypertension. Curr Hypertens Rep 3:139–144; 2001.[Medline]
- Somlyo A, Wu X, Walker L, Somlyo A. Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134:201–234; 1999.[Medline]
- Eto M, Ohmori T, Suzuki M, Furuya K, Morita F. A novel protein phosphatase-1 inhibitory protein potentiated by protein kinase C: isolation from porcine aorta media and characterization. J Biochem (Tokyo) 118:1104–1107; 1995[Abstract/Free Full Text]
- Eto M, Senba S, Morita F, Yazawa M. Molecular cloning of a novel phosphorylation-dependent inhibitory protein of protein phosphatase-1 (CPI17) in smooth muscle: its specific localization in smooth muscle. FEBS Lett 410:356–360; 1997.[Medline]
- Li L, Eto M, Lee MR, Morita F, Yazawa M, Kitazawa T. Possible involvement of the novel CPI-17 protein in protein kinase C signal transduction of rabbit arterial smooth muscle. J Physiol 508:871–881; 1998.[Abstract/Free Full Text]
- Kitazawa T, Eto M, Woodsome TP, Brautigan DL. Agonists trigger G protein-mediated activation of the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility. J Biol Chem 275:9897–9900; 2000.[Abstract/Free Full Text]
- Wu X, Haystead TAJ, Nakamoto RK, Somlyo AV, Somlyo AP. Acceleration of myosin light chain dephosphorylation and relaxation of smooth muscle by telokin: synergism with cyclic nucleotide-activated kinase. J Biol Chem 273:11362–11369; 1998.[Abstract/Free Full Text]
- Choudhury N, Khromov A, Somlyo A, Somlyo A. Telokin mediates Ca(2+)-desensitization through activation of myosin phosphatase in phasic and tonic smooth muscle. J Muscle Res Cell Motil 25:657–665; 2004.[Medline]
- Thiesen S, Kubart S, Ropers H-H, Nothwang HG. Isolation of two novel human RhoGEFs, ARHGEF3 and ARHGEF4, in 3p13–21 and 2q22. Biochem Biophys Res Commun 273:364–369; 2000.[Medline]
- Jin L, Ying Z, Webb RC. Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am J Physiol Heart Circ Physiol 287:H1495–H1500; 2004.[Abstract/Free Full Text]
- Gunst S, Tang D. The contractile apparatus and mechanical properties of airway smooth muscle. Eur Respir J 15:600–616; 2000.[Abstract]
- Gerthoffer WT, Gunst SJ. Signal transduction in smooth muscle (invited review): focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle. J Appl Physiol 91:963–972; 2001.[Abstract/Free Full Text]
- Tseng S, Kim R, Kim T, Morgan KG, Hai CM. F-actin disruption attenuates agonist-induced [Ca2+], myosin phosphorylation, and force in smooth muscle. Am J Physiol Cell Physiol 272:C1960–C1967; 1997.[Abstract/Free Full Text]
- Katsuyama H, Wang C, Morgan K. Regulation of vascular smooth muscle tone by caldesmon. J Biol Chem 267:14555–14558; 1992.[Abstract/Free Full Text]
- Winder S, Walsh M, Vasulka C, Johnson J. Calponin-calmodulin interaction: properties and effects on smooth and skeletal muscle actin binding and actomyosin ATPases. Biochemistry 32:13327–13333; 1993.[Medline]
- Sutherland C, Walsh M. Phosphorylation of caldesmon prevents its interaction with smooth muscle myosin. J Biol Chem 264:578–583; 1989.[Abstract/Free Full Text]
- Hedges JC, Oxhorn BC, Carty M, Adam LP, Yamboliev IA, Gerthoffer WT. Phosphorylation of caldesmon by ERK MAP kinases in smooth muscle. Am J Physiol Cell Physiol 278:C718–C726; 2000.[Abstract/Free Full Text]
- Yamboliev IA, Hedges JC, Mutnick JL-M, Adam LP, Gerthoffer WT. Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway. Am J Physiol Heart Circ Physiol 278:H1899–H1907; 2000.[Abstract/Free Full Text]
- Lavoie J, Hickey E, Weber L, Landry J. Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem 268:24210–24214; 1993.[Abstract/Free Full Text]
- Zhang D, Jin N, Rhoades R, Yancey K, Swartz D. Influence of microtubules on vascular smooth muscle contraction. J Muscle Res Cell Motil 21:293–300; 2000.[Medline]
- Platts SH, Falcone JC, Holton WT, Hill MA, Meininger GA. Alteration of microtubule polymerization modulates arteriolar vasomotor tone. Am J Physiol Heart Circ Physiol 277:H100–H106; 1999.[Abstract/Free Full Text]
- Chitaley K, Webb RC. Microtubule depolymerization facilitates contraction of rat aorta via activation of Rho-kinase. Vascul Pharmacol 38:157–161; 2002.[Medline]
- Chitaley K, Webb R. Microtubule depolymerization facilitates contraction of vascular smooth muscle via increased activation of RhoA/Rho-kinase. Med Hypotheses 56:381–385; 2001.[Medline]
- Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, Lewis RL, Mills TM, Hellstrom WJG, Kadowitz PJ. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A 101:9121–9126; 2004.[Abstract/Free Full Text]
- Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Hiroki J, Kaibuchi K, Takeshita A. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J 15:1062–1064; 2001.[Free Full Text]
- Kandabashi T, Shimokawa H, Mukai Y, Matoba T, Kunihiro I, Morikawa K, Ito M, Takahashi S, Kaibuchi K, Takeshita A. Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries. Arterioscler Thromb Vasc Biol 22:243–248; 2002.[Abstract/Free Full Text]
- Yoshii A, Iizuka K, Dobashi K, Horie T, Harada T, Nakazawa T, Mori M. Relaxation of contracted rabbit tracheal and human bronchial smooth muscle by Y-27632 through inhibition of Ca2+ sensitization. Am J Respir Cell Mol Biol 20:1190–1200; 1999.[Abstract/Free Full Text]
- Seasholtz TM, Brown JH. Rho signaling in vascular diseases. Mol Interv 4:348–357; 2004.[Abstract/Free Full Text]
Top
Abstract
Introduction
