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From the University of Pennsylvania, Philadelphia, Pennsylvania.
| Correspondence to: Michael E. DiSanto, 3010 Ravdin Courtyard, 3400 Spruce St, Philadelphia, PA 19104 (e-mail: mdisanto{at}mail.med.upenn.edu). |
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CCSM Contractility
The CCSM, unlike most other SMs, remains contracted the majority of the
time and then relaxes to carry out its physiological function (erection).
Unlike skeletal and cardiac muscle, which are regulated by calcium through a
tropomyosin-troponin complex, the initiation of contraction in all SM involves
a phosphorylation-dephosphorylation pathway that was originally thought to be
activated only by an elevation of cytosolic calcium
[Ca2+]I (Adelstein
and Eisenberg, 1980). An increase in [Ca2+]I
activates a Ca2+-calmodulin-dependent myosin light chain kinase
(MLCK) which phosphorylates the 20-kDa regulatory light chain of SMM (see
Figure 2B) at Ser19
and shows a direct correlation with an increase in actin-activated ATP
hydrolysis and associated cross-bridge cycling needed for generation of force
(Gorecka et al, 1976;
Chacko et al, 1977;
Sobieszek and Small, 1977;
Hai and Murphy, 1988). The
level of cytosolic calcium then returns to resting levels which inactivates
MLCK, and then the myosin is dephosphorylated by SMM phosphatase (SMMP)
(Hartshorne et al, 1998),
leading to SM relaxation (for summary, see
Figure 3, lower right
quadrant).
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Thus, treatment of ED requires the development of therapeutic agents that affect the contraction and relaxation of the CCSM. A better understanding of the molecular mechanisms that regulate contraction in the CCSM is critical to achieve this. Indeed, it has been found that even if the primary site of damage is neurogenic or vasculogenic in origin, normal erectile function can be achieved as long as sufficient SM relaxation is restored (Christ, 1995).
Actin-Myosin Interaction— The ability of SM to contract has been shown to be dependent upon the interaction between the major contractile proteins, actin and myosin (Figure 2A). A sliding filament model, described in detail for striated muscle contraction (Adelstein and Eisenberg, 1980; Chacko and Longhurst, 1995), also applies to SM, although the contractile apparatus in SM is not as highly ordered as in striated muscle.
SMM Isoforms—
In addition to the level of phosphorylation of SMM, the myosin isoform
composition can also influence the contractility of SM. Myosin II is the
molecular motor for contraction in all types of muscles. In general, the
velocity of force generation by a muscle is determined by the ATPase activity
of the myosin II when it interacts with actin
(Barany, 1967). SMM is a type
II myosin that is composed of a pair of myosin heavy chains (MHCs) and 2 pairs
of myosin light chains (MLCs) (Figure
2B). The MHCs wrap around each other to form an 
-helical
carboxyl-terminal tail and 2 amino-terminal globular heads. Each head contains
an actin-binding site and an active site for ATP hydrolysis needed to drive
the myosin head along the actin filament to produce force
(Adelstein and Eisenberg, 1980)
(Figure 2B).
Unlike skeletal or cardiac myosin in which different myosin isoforms are generally encoded by different genes, the mRNAs which encode the 4 vertebrate SMM heavy chain (SMMHC) isoforms identified to date originate from a single SMMHC gene through 2 alternative splice mechanisms (Figure 4). Two SMMHC isoforms, SM1 (204 kDa) and SM2 (200 kDa), which are different at the C-terminal region, are formed by alternative splicing at the 3' end (Babij and Periasamy, 1989). A recent study shows that increasing the SM1:SM2 ratio in SM has a significant effect on contractile function (Pyne et al, 2002), possibly by stabilizing the thick filament through tail-region interaction with the head of an adjacent myosin molecule (Rovner et al, 2002).
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Alternative splicing at the 5' end of the pre-mRNA also produces 2 SMMHC isoforms, SM-A and SM-B, which are different at the N-terminal region (Babij et al, 1991) (Figure 4). The SM-B isoform contains a 7 amino-acid insert near the ATP-binding site (encoded by a 21-nt insert in the mRNA), and this insert is absent in the SM-A isoform (Babij, 1993; Kelley et al, 1993). The presence of SM-B correlates with increased actin-activated Mg2+-ATPase activity, increased velocity of movement of actin filaments in vitro, and increased maximum velocity of SM shortening compared with aortic SMM, which completely lacks this insert (Kelley et al, 1993; DiSanto et al, 1997; Babu et al, 2001). In general, more SM-B is found in SMs that show a strong phasic-like response to stimulation (eg, urinary bladder and esophageal body), whereas greater amounts of SM-A are present in SMs that are more tonic-like (eg, aortic and lower esophageal sphincter) (Kelley et al, 1993; DiSanto et al, 1997; Szymanski et al, 1998; Hypolite et al, 2001). The rabbit and human CCSM contain an intermediate percentage of SM-B (about 35%) (DiSanto et al, 1998b). We have found that the amount of SM-B is decreased to virtually zero in men diagnosed with ED (DiSanto et al, 1998a).
One of the pairs of MLCs, known as the essential light chains, also exist as 2 different isoforms generated via alternative splicing of a single gene (Nabeshima et al, 1987; Lenz et al, 1989). These 2 isoforms, known as LC17a and LC17b, are identical except for 5 of the last 9 carboxyl-terminal amino acids (Hasegawa et al, 1988). Because a greater ratio of LC17b to LC17a is found in tonic-type muscles than in more phasic muscles, it has been proposed that the LC17a/LC17b isoform composition in a particular SM may help determine its tonicity (Helper et al, 1988; Malmqvist and Arner, 1991). Our laboratory has found that rabbit CCSM contains about 13% LC17b and thus 87% LC17a (DiSanto et al, 1998b) compared with the phasic-type normal rabbit bladder that expresses almost 100% LC17a and the tonic-type normal rabbit aorta which expresses almost equal amounts of LC17a and LC17b.
RhoA/ROK Pathway— More recently, it has been shown that SM contraction can also occur even in the absence of changes in [Ca2+]I by inhibiting SMMP (Somlyo et al, 1989; Kitazawa et al, 1991) via a guanine nucleotide-binding protein (G protein)-coupled mechanism. This process has been termed calcium sensitization of SM because inhibiting the SMMP does not require calcium and allows the MLCK to work more efficiently, leading ultimately to increased force. RhoA, a member of the Rho subfamily of Ras proteins, becomes active when bound to guanosine triphosphate (GTP) and activates an enzyme known as ROK (Matsui et al, 1996). Activated ROK has been proposed to increase the phosphorylation level of SMM either by directly phosphorylating the myosin (Amano et al, 1996) or indirectly by inhibiting the phosphatase responsible for dephosphorylating SMM (Kimura et al, 1996). Thus, ROK activity is regulated through a complex molecular pathway, the participants of which are just starting to be identified. A brief summary of the major participants in this pathway and how these pathways are thought to interact is shown in Figure 3.
ROK has been classified into 2 isoforms: ROK and ROKß, also
referred to as ROCK-II and ROCK-I, respectively
(Nakagawa et al, 1996). These
isoforms are relatively large proteins (150-160 kDa) consisting of an
amino-terminal kinase domain, a central coiled-coil domain that includes a
Rho-binding domain, and a carboxyl-terminal putative pleckstrin homology
domain. Although the kinase domain is more than 90% conserved between
ROK and ROKß in the mouse, the rest of the molecules are only
around 55% to 70% conserved, suggesting that the 2 enzymes may have somewhat
different cellular functions (Nakagawa et
al, 1996). Although data have shown that both rabbit and human
CCSM express both isoforms of ROK (Chang
et al, 2000; Wang et al,
2002), in certain pathological conditions such as diabetes
(Chang et al, 2002a) and
partial bladder outlet obstruction (Chang
et al, 2002b), expression of the ROKß isoform in the CCSM
appears to be altered more than does expression of the ROK isoform, at
least in the rabbit.
The inhibitor Y-27632, a selective inhibitor of ROK
(Uehata et al, 1997), has been
shown to have little effect on the initial transient increase in force in the
coronary artery, but it nearly abolished the sustainment of force in this
muscle (Nobe and Paul, 2001). Thus, along with confirming a role for ROK in calcium sensitization of SM, the
above study suggests that ROK should play a major role in keeping the CCSM in
the flaccid (tonically contracted) state. Using permeabilized CCSM strips in
which calcium concentrations were clamped, Wang et al
(2002) found that the
GTP
S-induced Ca2+-sensitization in CCSM was 2 times higher
than that reported for other SMs, again suggesting an important role for
RhoA/ROK in CCSM contraction. Chitaley et al
(2001) demonstrated the in
vivo importance of ROK to CCSM tone when they showed that administration of
the ROK inhibitor Y-27632 to normal rats resulted in penile erection.
Chitaley and Webb (2002) suggested that the mechanism by which nitric oxide (NO) causes vascular SM relaxation involves inhibition of ROK signaling. The mechanistic link between these 2 pathways appears to be the enzyme known as cyclic guanosine monophospate (cGMP)-dependent protein kinase-1 (PKG-1), which will be discussed in more detail in the following section. An increased production of NO is known to increase the levels of cGMP and hence activate PKG-1. Because PKG-1 has been shown to phosphorylate RhoA, thus inhibiting its ROK activating ability (Sawada et al, 2001), an increase in NO can lead to inactivation of the ROK pathway (see PKG in schematic of Figure 3—double green arrow indicates blocking RhoA translocation to membrane by phosphorylation).
cGMP-Dependent protein kinase (PKG-1)— cGMP appears to be the main mediator of relaxation in the CCSM. In response to sexual stimuli, release of NO from nonadrenergic, noncholinergic nerve terminals causes elevation of cGMP via stimulation of guanylate cyclase activity, which then leads to relaxation of the CCSM and eventually to penile erection. Phosphodiesterase 5 (PDE5) can break down cGMP to GMP, and it is this reaction that is targeted and blocked by PDE5 inhibitors such as sildenafil (Viagra), Vardenafil (Levitra), and Tadalifil (Cialis). However, the exact mechanism by which cGMP causes CCSM relaxation remains unclear, although the pathway is proposed to involve activation of PKG-1 (Lincoln et al, 1995). The physiological relevance of the PKG-1 enzyme in SM has been demonstrated by knocking out the PKG-1 gene in mice. These mice have been shown to completely lack NO-cGMP-dependent SM relaxation and exhibit hyperactive voiding patterns (Persson et al, 2000). More relevant to this review is that these PKG-1 knockout mice have a very limited ability to reproduce, which appears to be the result of the inability of their CCSM to relax upon activation of the NO/cGMP signaling pathway (Hedlund et al, 2000).
cGMP-dependent protein kinases (termed PKGs or cGKs) are classified into 2
types, PKG-I and PKG-II, based on their historical order of characterization.
In general, PKG-II is membrane bound, whereas PKG-I is found in the soluble
fraction of the cell. There are 2 PKG-I isoforms, PKG-I (76 kDa) and
PKG-Iß (78 kDa), which arise from the alternative splicing of a single
gene (Francis et al, 1988;
Wolfe et al, 1989). These 2
isoforms differ in their amino-terminal autoinhibitory domains but are
identical in their cGMP-binding sites and catalytic domains. PKG-I is
highly expressed in the Purkinje cells of the cerebellum, in platelets, in
lung, and in SM cells, whereas the PKG-Iß isoform is primarily expressed
in SM cells (Keilbach et al,
1992; Collins and Uhler,
1999). Our laboratory has recently shown that the expression of
PKG-1 is selectively downregulated in CCSM in response to diabetes and
that this decreased expression correlates with a decrease of in vitro PKG
activity (Chang et al,
2002c).
Endothelin (ET)— The ETs are a family of 21 amino-acid peptides consisting of ET-1, ET-2, and ET-3 (Yanagisawa et al, 1988), each the product of a separate gene and differing from one another by only a few amino acids (Luscher and Barton, 2000). The relative expression of the ET isoforms varies in different tissues, with ET-1 being the predominant ET in normal plasma (Usuki et al, 2000) and proposed to play the biggest role in regulating CCSM contractility. Recent studies have suggested that ET-1 plays an important role as a modulator of erectile physiology and dysfunction (Saenz et al, 1991; Christ et al, 1995). Although endothelial cells are a major source of ET, vascular SM cells (Hahn et al, 1990; Kanse et al, 1991), as well as the CCSM itself (Saenz et al, 1991; Saenz et al, 1992), can also produce ET. Thus, ET can be released from the endothelial cells either lining the arteries within the CC or lining the CCSM and also directly from the CCSM itself. Interestingly, the level of ET produced by vascular SM cells is elevated in pathophysiological states, including hypertension and atherosclerosis (Haug et al, 1996; Lu et al, 2001).
The biological effects of ET-1 appear to be mediated by 2 main subtypes of ET receptors, which are referred to as ETA and ETB, and are encoded by separate genes (Nakamuta et al, 1991; Sakamoto et al, 1991). Activation of the ETB receptor has been shown to cause a transient vasodilation (Matsuda et al, 1993), whereas activation of either the ETA or the ETB receptor can cause a sustained contraction of SM (Sumner et al, 1992). Thus, the relative expression of these ET receptors may be crucial for defining the contractile state of the CCSM. Although both ETA and ETB receptors exist in mammalian CCSM (Bell et al, 1995), including human (Christ et al, 1995), from the current knowledge, ET-1-induced CCSM contraction appears to be mediated predominantly by ETA receptors. Our work has shown that in response to diabetes, the sensitivity of the CCSM to ET-1 is increased threefold, and the mechanism for this increase appears to involve an up-regulation of the ETA receptor (Chang et al, 2002a) (Figure 5). This finding of an up-regulation of ETA receptor expression in response to diabetes is also supported by a receptor-binding study that found increased ET binding by ETA receptors in rats with diabetes compared with normal rats (Bell et al, 1995). Our finding that ET-1-induced contraction of CCSM can be almost completely inhibited by pretreatment with the ROK inhibitor Y-27632 (Chang et al, 2002a) suggests that ET-induced contraction in CCSM is largely dependent upon the RhoA/ ROK signal transduction pathway.
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Hormonal Regulation of CCSM
Although many clinical studies have shown that decreased testosterone
levels are associated with loss of libido and ED in humans
(Burris et al, 1992;
Wang et al, 1996), these
changes have been thought to be centrally mediated rather than having a direct
effect on human CCSM (Wespes,
2002). However, in animals there is much evidence that suggests
that testosterone levels can directly affect the contractility of the CCSM.
For example, it was determined that androgens affect the responsiveness of SM
to electrostimulation in as much as castration resulted in a reduction in the
maximal ICP achieved during erection
(Mills et al, 1992). Moreover,
this study determined that the responsiveness of the SM could be returned to
normal levels by administration of exogenous testosterone. These results were
confirmed by a separate study that showed that administering testosterone
after castration resulted in an increased number of erections in response to
apomorphine in a dose-dependent manner
(Heaton and Varrin, 1994).
The fact that aging in rats is associated with a decline in both serum testosterone levels and erectile function and normal erectile responses can be restored with long-term administration of testosterone alone (Wang et al, 1993) also supports a role for androgens in erectile function. Interestingly, the SM of the rat penis contains androgen receptors, and it has been hypothesized that it may be integral to the erectile process because SM cells predominate in the penis (Geneser, 1986). There is also an age-related decrease in the number of androgen receptors in the penile SM but not in the penile skin or urethra. Thus, testosterone does appear to have a direct effect on the penile tissue itself.
Sex Hormones and SM Contractility— It has been demonstrated that the CCSM from castrated rabbits exhibits increased contraction to high K+ solution (Holmquist et al, 1994), whereas relaxation of phenylephrine precontracted CCSM from castrated rabbits by field stimulation or sodium nitroprusside (Itoh et al, 1996) is significantly reduced compared with sham-operated controls. Similarly, precontracted CCSM from castrated rats has been found to be more difficult to relax either by sodium nitroprusside or by cGMP compared with sham-operated controls (Alcorn et al, 1999). Furthermore, in animal models, application of exogenous testosterone has been shown to increase CCSM relaxation by field stimulation (Li et al, 2002), sodium nitroprusside (Li et al, 2002) and carbachol (Yildirim et al, 2000). Although a positive correlation between testosterone level and NO synthase expression in the corporal tissue has been established (Penson et al, 1996, 1997; Reilly et al, 1997; Schirar et al, 1997; Marin et al, 1999; Park et al, 1999; Seo et al, 1999), the exact cause of androgen-induced altered CCSM contractility is not known. The following 2 paragraphs provide evidence to suggest that changes in the CCSM contractile apparatus may play a role in androgen regulation of CCSM contractility.
It has been shown that castration reduces the SM content of the CC in rabbits and that testosterone can restore normal SM content (Traish et al, 1999). Our laboratory has provided evidence suggesting that decreasing sex hormones downregulates SMM expression. Using a rabbit model, we showed that expression of bladder SMM was decreased in ovariectomized animals, and this decrease could be reversed by administration of 17-ß estradiol (Sanchez-Ortiz et al, 2001). Furthermore, we showed in this study that the ratio of the SM2-to-SM1 SMMHC isoform composition was significantly decreased (which may stabilize the thick filament leading to increased contractility as described above) and could be returned to normal by restoring estrogen levels (Figure 6). Similar findings have also been made regarding testosterone levels. For example, the expression of SMM in the dog prostatic stroma was shown to decline rapidly after castration (Niu et al, 2001), but the isoform composition has not been characterized. Because the castrated dogs in this study were shown to have a significantly decreased expression of circulating testosterone while their estradiol levels remained unchanged, it is suggested that decreased testosterone as well as estrogen levels can downregulate SMM expression.
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Supporting the above studies is the fact that estradiol and testosterone as well as dihydrotestosterone have been shown to increase the expression of SMM in cultured human prostatic stromal SM cells (Zhang et al, 1997; Niu et al, 2001). Also, differential steroid hormone effects have been observed. In the uterus, testosterone but not estrogen normalized the ovariectomy-induced decreased expression of SM1 and strongly increased the expression of 5'-inserted MHC known as SM-B (described above), whereas estrogen but not testosterone normalized the ovariectomy-induced diminished MLC17a expression (Calovini et al, 1995). Additionally, it has recently been demonstrated in rats that castration induces programmed cell death and that subsequent administration of testosterone to these castrated animals initiates new DNA synthesis in many cell types, including the myocytes (Shabsigh, 1997). If this is true, the new SM cell population may possess an altered myosin isoform composition.
Sex Hormones and RhoA/ROK— Although no clear link between sex hormone levels and the RhoA/ROK pathway has been established, there are some studies which suggest a link between RhoA/ROK activity and hormone receptors. Inhibition of RhoA has been demonstrated to enhance estrogen receptor alpha expression, whereas overexpression of constitutively active forms of RhoA results in decreased estrogen receptor transcriptional activity (Su et al, 2001). Also, androgen receptor activity can be controlled by the RhoA effector protein C-related kinase (Metzger et al, 2003). In addition, stimulation of the Rho signaling pathway has been shown to activate androgen-receptor-dependent genes (Muller et al, 2002). Understanding the exact relationship between the RhoA/ROK pathway and androgens in the CCSM awaits further study.
Sex Hormones and PKG-1— At present, no direct affects of androgens on PKG have been demonstrated. However, coronary artery SM from normal female rats contracts more in response to the PKG antagonist KT 5283 than do arteries from ovariectomized rats, suggesting a decreased amount or activity of PKG in the ovariectomized animals (Wellman et al, 1996). Similarly, coronary artery SM from female rats contracts more to KT 5283 than do arteries from male rats (Wellman et al, 1996). Also, progesterone, either by itself or in combination with estrogen, has been shown to decrease PKG activity (Sheffield et al, 1987). Although these effects were originally thought to be mediated primarily through activation of K+ activated channels (White et al, 1995), the more recent findings of a role for PKG in the RhoA/ ROK pathway (described above) may suggest a possible role for estrogens in the direct regulation of the SM contractile apparatus. The finding that testosterone can cause direct relaxation of arterial SM (Chou et al, 1996; Costarella et al, 1996) suggests that androgens may also have an effect on PKG.
Sex Hormones and ET— Castration of male rats was associated with a two- to fourfold increase in the expression of prostatic ET receptors, suggesting a role for androgens in regulating ET receptor expression (Takahashi et al, 2002). This same study also found an increase in ET-1 as well as ET-converting enzyme-1 mRNA, again supporting a role for androgens in regulating the pathway of ET-induced contraction. Similarly, an increased expression of ET receptors in castrated male dogs has been observed (Padley et al, 2002). Indeed, testosterone appears to have an effect on ET-1-induced CCSM contractility as well. Experimental hypogonadism induced in rabbits by the long-acting gonadotropin-releasing hormone analog triptorelin palmoate decreased the ability of yohimbe (a drug derived from tree bark with beneficial effects on erection) to relax ET-1 precontracted rabbit CCSM, whereas testosterone supplementation to the rabbits with hypogonadism not only restored but enhanced the CCSM relaxing ability of yohimbe (Filippi et al, 2002). Although these authors hypothesize that the mechanism by which decreased testosterone levels attenuate relaxation by yohimbe is through a down-regulation of NO production, it is also possible that the decreased testosterone levels may elevate expression of the ET receptors or ET-1, as has been shown for the prostate, thus making it harder for yohimbe to relax ET-1 precontracted CCSM.
Experimental diabetes in rats also causes an up-regulation of prostatic ET receptors, and it was found that serum testosterone levels were reduced in these animals (Saito et al, 1996). This observation suggests that our finding of increased CCSM sensitivity to ET-1 modulated through an overexpression of ET receptors in rabbits with diabetes compared with normal rabbits (described above) may, at least partly, result from a decrease in serum testosterone levels associated with the diabetes. Thus, the expression of ET-1 and ET receptors in the CCSM of castrated and testosterone-supplemented animals will be interesting to examine along with the effects of ET-receptor-specific antagonists.
Summary
The proper functioning of the CCSM is necessary for the normal erectile
process. As outlined in this article, there are many molecular mechanisms that
function at the level of the SM and are capable of regulating CCSM
contractility. These mechanisms include phosphorylation of the SMM, alteration
of SMM isoform composition, and modulations in the expression of participants
involved in the recently emerging calcium sensitization pathways of SM
contraction, including the ET/ROK pathway. Understanding these molecular
control mechanisms as well as the influence that hormones have on these
pathways should provide new and novel targets for drug development to treat
ED.
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Footnotes |
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