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Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior

Department of Ob/Gyn, University of Vermont College of Medicine, Burlington, Vermont 05405, USA

¹Correspondence: Departments of Ob/Gyn, Pharmacology and Neurology, University of Vermont College of Medicine, Given C454, Burlington, VT 05405, USA. E-mail: mcipolla{at}zoo.uvm.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION ACTIN CYTOSKELETAL CHANGES IN... THE ROLE OF ACTIN... EVIDENCE FOR ACTIN... REFERENCES

 
We hypothesize that actin polymerization within vascular smooth muscle (VSM) in response to increased intravascular pressure is a novel and previously unrecognized mechanism underlying arterial myogenic behavior. This hypothesis is based on the following observations. 1) Unlike skeletal or cardiac muscle, VSM contains a substantial pool of unpolymerized globular (G) actin whose function is not known. 2) The cytosolic concentration of G-actin is significantly reduced by an elevation in intravascular pressure, demonstrating the dynamic nature of actin within VSM and implying a shift in the F:G equilibrium in favor of F-actin. 3) Agents that inhibit actin polymerization and stabilize the cytoskeleton (cytochalasins and latrunculin) inhibit the development of myogenic tone and decrease the effectiveness of myogenic reactivity. 4) Depolymerization of F-actin with cytochalasin D causes VSM relaxation and increased G-actin content, whereas polymerization of F-actin with jasplakinolide causes VSM contraction and decreased G-actin content. These results are consistent with observations in other cell types in which actin dynamics have been implicated in contractility and/or motility. Actin filament formation in VSM may therefore underlie mechanotransduction and, by providing additional sites for interaction with myosin, enhance force production in response to pressure. Although the mechanism by which actin polymerization is stimulated by pressure is not known, it likely occurs via integrin-mediated activation of signal transduction pathways previously associated with VSM contraction (e.g., PKC activation, Rho A, and tyrosine phosphorylation).—Cipolla, M. J., Gokina, N. I., Osol, G. Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior.

Key Words: myogenic reactivity • mechanotransduction • cytoskeletal rearrangement

	INTRODUCTION

TOP ABSTRACT INTRODUCTION ACTIN CYTOSKELETAL CHANGES IN... THE ROLE OF ACTIN... EVIDENCE FOR ACTIN... REFERENCES

 
VASCULAR SMOOTH MUSCLE (VSM) responds to increased intravascular pressure with contraction, thereby allowing diameter and blood flow to be regulated in response to changes in arterial blood pressure (1 , 2) . However, for arterial diameter to be maintained in response to increased intravascular pressure and control cerebral blood flow (CBF), VSM force production must increase in order to counteract the increased wall tension (3) . This myogenic response is particularly well developed in the arteries of the cerebral circulation and underlies both cerebrovascular resistance and autoregulation of CBF (1 , 2) .

	ACTIN CYTOSKELETAL CHANGES IN RESPONSE TO MECHANICAL STIMULI

TOP ABSTRACT INTRODUCTION ACTIN CYTOSKELETAL CHANGES IN... THE ROLE OF ACTIN... EVIDENCE FOR ACTIN... REFERENCES

 
Whereas there has been considerable progress in understanding the signal transduction mechanisms involved in myogenic activity, the exact subcellular events that afford VSM the ability to increase force production in response to pressure are still not clear (4) . In other nonmuscle cell types, including fibroblasts and endothelial cells, force production in response to mechanical stimuli such as tension or stretch is accomplished through actin cytoskeletal rearrangement and the formation of contractile stress fibers (5 , 6) . Although little is known about the dynamic nature of the VSM actin cytoskeleton, striking similarities exist between smooth muscle and nonmuscle cells to suggest analogous structural and functional roles in response to mechanical stimuli.

First, VSM is the least specialized type of muscle and is phenotypically and morphologically more similar to nonmuscle cells (e.g., fibroblasts) than to striated or cardiac muscle in that smooth muscle does not have distinct myofibrils (7) . The spatial organization of the loosely arranged contractile apparatus of VSM is ill-defined, with no apparent sarcomeric structure. Hence, the ultrastructural basis underlying force generation is not well understood, although thin filament regulation of contraction is well established in smooth muscle (8) .

Second, both smooth muscle and nonmuscle cells respond to mechanical stimuli such as tension or cyclic strain with actin cytoskeletal rearrangement that is associated with increased contraction (9 , 10) . In addition, both smooth muscle and nonmuscle cells maintain a relatively large proportion (30–40%) of total actin in an unpolymerized, globular (G) form (11 , 12) . As a result, the F:G-actin ratio in smooth muscle is on the order of 1:1 or 2:1, whereas only 11–13% of the actin in striated muscle exists as G-actin, yielding an F:G-actin ratio of 8:1 or 9:1. Hence, VSM is unique because it contains a large substrate pool of G-actin available for polymerization into filaments.

Third, the biochemical regulation of contraction, which is thought to be accomplished through the calcium/calmodulin complex binding to and activating of myosin light chain kinase, is distinctly different from that of cardiac or skeletal muscle, but similar to that of contractile stress fibers in nonmuscle cells (13) .

Finally, the same signal transduction pathways and second messengers that have been shown to regulate the dynamics of actin polymerization and stress fiber formation in nonmuscle cells in response to mechanical stimuli have been proposed as mechanisms of mechanotransduction and myogenic reactivity in VSM (e.g., phospholipid hydrolysis, tyrosine kinase and PKC activity, G protein/Rho A activation, and calcium mobilization) (14 15 16 17) .

Together, these observations suggest that, similar to nonmuscle cells, smooth muscle has the ability to respond to physical forces such as tension with actin cytoskeletal rearrangement, and that this mechanism may contribute to vascular myogenic activity.

	THE ROLE OF ACTIN POLYMERIZATION IN SMOOTH MUSCLE CONTRACTION

TOP ABSTRACT INTRODUCTION ACTIN CYTOSKELETAL CHANGES IN... THE ROLE OF ACTIN... EVIDENCE FOR ACTIN... REFERENCES

 
A few studies have investigated the dynamic nature of actin in smooth muscle and provide evidence for the importance of cytoskeletal dynamics in contraction. Mauss et al. showed that inhibition of actin polymerization by Clostridium botulinum C2 toxin (which ADP-ribosylates G-actin) impaired the contraction of smooth muscle isolated from guinea pig ileum (18) . Because F-actin is not a substrate for C2 toxin, these findings provide evidence for a role of G- to F-actin transition in smooth muscle contraction. In a related study in which actin polymerization was blocked by cytochalasin B, depolarization-induced contraction of intestinal smooth muscle cells was inhibited in a dose-dependent manner, without any significant effect on voltage-dependent calcium channels, membrane potential, or myosin light chain phosphorylation, indicating an influence of actin assembly on smooth muscle cell contraction (19) .

The G-actin pool in smooth muscle has been shown to be modulated during contraction, providing evidence for changes in the F:G-actin ratio. For example, the amount of G-actin content in tracheal smooth muscle, measured by DNase I inhibition, decreased by 30% when stimulated to contract by acetylcholine (20) . This decrease in G-actin was inhibited by latrunculin-A, a compound that prevents actin polymerization by binding G-actin monomers. In the same study, latrunculin-A decreased force production induced by acetylcholine without affecting myosin light chain phosphorylation, further suggesting that actin polymerization contributes directly to force development.

The dynamic role of actin polymerization in response to a mechanical stimulus was recently demonstrated in airway smooth muscle (9) . Smith and colleagues used cultured airway smooth muscle subjected to cyclic deformational strain to show that mechanical strain increases contractility. Maximal force production in cells subjected to cyclic strain was accompanied by actin cytoskeletal reorganization without any increase in MLCK content, suggesting that actin filament formation in response to mechanical stimulation is a mechanism by which smooth muscle can increase force production.

	EVIDENCE FOR ACTIN POLYMERIZATION AS A MECHANISM UNDERLYING MYOGENIC CONTRACTION

TOP ABSTRACT INTRODUCTION ACTIN CYTOSKELETAL CHANGES IN... THE ROLE OF ACTIN... EVIDENCE FOR ACTIN... REFERENCES

 
Our own findings in isolated and pressurized cerebral arteries specifically support a role for actin polymerization in mediating myogenic activity. The advantage of using isolated arterial segments to study myogenic mechanisms is that arteries can be exposed to the primary stimulus (pressure/stretch) under conditions that are both controlled and devoid of the confounding influences of tissue metabolites and neurotransmitters released from periarterial nerves (9) . In this preparation as well as in vivo, myogenic tone usually develops between 40 and 60 mmHg and is maintained over a wide range of transmural pressures (50–150 mmHg) (4) . For example, cerebral arteries that were cannulated and pressurized to either 75 or 125 mmHg had similar diameters (133±11 vs. 136±4 µm, P>0.05), even though wall tension was increased >70% (662 vs. 1129 dynes/cm²) at the higher pressure. It follows that smooth muscle force production must increase proportionately to counteract the increased wall tension in order to maintain a constant diameter. We found that whereas diameter was similar at the different pressures, G-actin content was significantly decreased at the higher pressure. These same arteries were chemically fixed with formalin in a pressurized state (at 75 or 125 mmHg) and stained for G-actin with fluorescent-labeled DNase I. DNase I binds G-actin in a 1:1 ratio and is therefore easily quantified using confocal microscopy (21) . Arteries at the higher pressure of 125 mmHg had significantly less G-actin content than arteries at 75 mmHg (7.2±0.67 vs. 10.3±0.82 intensity of pixelsx10⁶, P<0.01), although wall tension was considerably elevated and diameter was maintained. These results demonstrate that an increase in the F:G-actin ratio accompanies the increased force production in VSM during myogenic contraction.

Other experimental evidence supports the hypothesis that the process of actin polymerization is important during myogenic contraction. For example, arteries exposed to low concentrations of cytochalasin B, a compound known to inhibit actin polymerization, have diminished capacity to respond to pressure myogenically. Figure 1 shows the diameter of cerebral arteries with tone after stepwise increases in pressure from 75 to 200 mmHg in the absence and presence of cytochalasin B. Arteries without cytochalasin maintained a fairly constant diameter over the myogenic pressure range from 75 to 150 mmHg (even though wall tension increased 81%), but arteries exposed to cytochalasin B dilated to the increased pressure and lacked a myogenic response. Further support for the importance of actin polymerization in myogenic activity was shown in a previous study in which cytochalasin B lowered the pressure at which forced dilatation (the pressure at which there is forcible loss of tone due to acute increases in intravascular pressure) occurred (22) . A similar finding is shown in Fig. 1 , where it is fairly obvious that arteries without cytochalasin B can resist pressure and force dilatate between 175–200 mmHg, whereas arteries exposed to cytochalasin B dilate to pressures as low as 125–150 mmHg.

View larger version (18K): [in this window] [in a new window]   Figure 1. Graph showing the diameter response of cerebral arteries after step increases in intravascular pressure from 75 to 200 mmHg. Arteries were either in the absence (filled circles) or presence (open circles) of 3.0 µM cytochalasin B, a cell-permeable inhibitor of actin polymerization. Arteries without cytochalasin responded to the increased pressure with myogenic contraction and maintenance of a relatively constant diameter. Arteries in the presence of cytochalasin B dilated to the increased pressure and lacked myogenicity. All measurements were taken after a steady state was reached, 15 min. The lack of a myogenic response in the presence of cytochalasin B suggests that the process of actin polymerization is important to pressure-induced myogenic contraction.

The role of actin polymerization in maintaining myogenic tone is shown in another set of experiments where higher concentrations of cytochalasin B caused vasodilation and inhibited basal myogenic tone in isolated cerebral arteries pressurized to 75 mmHg. Figure 2 shows the concentration response of arteries that started with tone and dilated to increasing concentrations of cytochalasin B. Since cytochalasin B inhibits actin filament formation, these results suggest that the process of actin polymerization is necessary for myogenic contraction. It is likely that new filament formation is important for increased force production in response to increased pressure.

View larger version (12K): [in this window] [in a new window]   Figure 2. Graph showing the concentration-response curve of pressurized cerebral arteries to cytochalasin B (n=7). Cytochalasin B was given to cannulated and pressurized cerebral arteries at 75 mmHg, which developed spontaneous myogenic tone. Increasing concentrations of cytochalasin B caused a concentration-dependent dilation and loss of myogenic tone.

Compounds that affect the G-actin pool have been shown to affect myogenic activity as well. For example, latrunculin-A is a compound that binds to G-actin monomers and prevents the formation of filaments. When this compound was given to pressurized cerebral arteries, the extent of tone developed in response to an increase in pressure was significantly diminished (27±2 without vs. 5±1% with 3.0 µM latrunculin-A, P<0.05). Since latrunculin-A acts to sequester G-actin and prevent actin polymerization, the lack of tone development in its presence strongly suggests the G- to F-actin transition to be an important underlying event.

The importance of a G- to F-actin transition in VSM contraction is further evidenced by experiments in which agents known to affect the state of polymerization of actin were given to cerebral arteries with tone at a constant pressure of 75 mmHg. Figure 3 A shows that the diameter of arteries that were given either cytochalasin D (to cause depolymerization of actin filaments) or jasplakinolide (to cause polymerization of actin filaments) and compared with arteries in the absence of these agents. Figure 3B shows the G-actin content of these same arteries, fixed pressurized and stained for G-actin with DNase I. G-actin content was determined using confocal microscopy. Notice that arteries given cytochalasin D dilated and lost tone whereas arteries given jasplakinolide constricted and increased tone. G-actin content followed a similar pattern: arteries that dilated in cytochalasin D had the greatest G-actin content and arteries constricted in jasplakinolide had the least amount of G-actin. Arteries with tone without exposure to these compounds maintained an intermediate diameter and had an intermediate amount of G-actin. These data strongly support the hypothesis that G-actin in VSM is labile and that its transition into F-actin is an important mediator of the state of VSM contraction.

View larger version (32K): [in this window] [in a new window]   Figure 3. A) Graph showing the diameter of cerebral arteries at 75 mmHg given either 0.1 µM jasplakinolide, a cell-permeable compound that causes actin polymerization (open bar), or 50 µM cytochalasin D, a compound that causes actin depolymerization (hatched bar), and compared to arteries in the absence of any compounds with tone (filled bar). Arteries that were given cytochalasin D dilated and lost tone whereas arteries given jasplakinolide constricted and increased the amount of tone, demonstrating that manipulation of the state of actin polymerization in VSM can modulate the level of myogenic tone in cerebral arteries. B) Graph showing the G-actin content of the same arteries shown in Fig. 3 A. Arteries given cytochalasin D that dilated and lost tone had the greatest G-actin content whereas arteries given jasplakinolide, which constricted and increased the amount of tone, had the least amount of G-actin. Arteries with tone had an intermediate amount of G-actin, demonstrating there is a labile pool of G-actin in VSM that can be induced to form filaments and affect arterial diameter.

Based on the evidence above, we hypothesize that actin polymerization in response to increased intravascular pressure is a mechanism whereby VSM can increase force production and maintain arterial diameter. Actin polymerization could lead to increased force production by VSM by increasing the number of sites available for actin–myosin interaction. This mechanism was demonstrated recently in airway smooth muscle that formed contractile stress fibers and produced increased force in response to cyclic strain (9) . Furthermore, being cytoskeletal structures, the change in F- and G-actin could affect load bearing structures within the cell and thereby alter the energy required for smooth muscle contraction, providing a mechanism whereby less force production is needed to counteract increased wall tension.

In summary, we hypothesize that increases in intravascular pressure via elevations in wall tension lead to mechanotransmission across the VSM cell membrane, resulting in the activation of signaling pathways (e.g., Rho-A, PLC, etc.) that lead to stimulation of actin polymerization (increased F:G ratio), formation of contractile stress fibers, and an increase in VSM force production (23 24 25 26) . This scheme, shown in Fig. 4 , is based on a combination of direct and indirect evidence from VSM and is consistent with observations in other cell types. Critical evaluation of this hypothesis will require additional studies focused on understanding the precise linkage between mechanotransduction and the 3-dimensional spatial organization of the associated cytoskeletal structures within arterial VSM. New thin filament formation in response to increased pressure may be a potentially important and unrecognized process underlying myogenic contraction.

View larger version (12K): [in this window] [in a new window]   Figure 4. Diagram showing the hypothesized mechanism of myogenic activity and the role of actin polymerization in mechanotransduction in VSM. An increase in wall tension leads to mechanotransmission across the VSM cell membrane resulting in the activation of signaling pathways (e.g., Rho-A, PLC, etc.), which result in stimulation of actin polymerization (increased F:G ratio), formation of contractile stress fibers. The subsequent actin filament formation and contractile stress fiber formation increase VSM force production, decrease diameter, and regulate blood flow.

	ACKNOWLEDGMENTS

 
This work was supported by National Institutes of Health National Heart, Lung and Blood Institute ROI 59406 (G.O.)

Received for publication May 16, 2001. Revision received August 8, 2001.

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TOP ABSTRACT INTRODUCTION ACTIN CYTOSKELETAL CHANGES IN... THE ROLE OF ACTIN... EVIDENCE FOR ACTIN... REFERENCES

 

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				A. Opazo Saez, W. Zhang, Y. Wu, C. E. Turner, D. D. Tang, and S. J. Gunst Tension development during contractile stimulation of smooth muscle requires recruitment of paxillin and vinculin to the membrane Am J Physiol Cell Physiol, February 1, 2004; 286(2): C433 - C447. [Abstract] [Full Text] [PDF]

				C. Ott, D. Iwanciw, A. Graness, K. Giehl, and M. Goppelt-Struebe Modulation of the Expression of Connective Tissue Growth Factor by Alterations of the Cytoskeleton J. Biol. Chem., November 7, 2003; 278(45): 44305 - 44311. [Abstract] [Full Text] [PDF]

				A. Y. Kolyada, K. N. Riley, and I. M. Herman Rho GTPase signaling modulates cell shape and contractile phenotype in an isoactin-specific manner Am J Physiol Cell Physiol, November 1, 2003; 285(5): C1116 - C1121. [Abstract] [Full Text] [PDF]

				D. D. Tang and J. Tan Downregulation of profilin with antisense oligodeoxynucleotides inhibits force development during stimulation of smooth muscle Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1528 - H1536. [Abstract] [Full Text] [PDF]

				S. P. Marrelli, M. S. Eckmann, and M. S. Hunte Role of endothelial intermediate conductance KCa channels in cerebral EDHF-mediated dilations Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1590 - H1599. [Abstract] [Full Text] [PDF]

				M. A. Hill, S. J. Potocnik, L. A. Martinez-Lemus, and G. A. Meininger Delayed arteriolar relaxation after prolonged agonist exposure: functional remodeling involving tyrosine phosphorylation Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H849 - H856. [Abstract] [Full Text] [PDF]

				S. J. Gunst and J. J. Fredberg The first three minutes: smooth muscle contraction, cytoskeletal events, and soft glasses J Appl Physiol, July 1, 2003; 95(1): 413 - 425. [Abstract] [Full Text] [PDF]

				A. Zeidan, I. Nordstrom, S. Albinsson, U. Malmqvist, K. Sward, and P. Hellstrand Stretch-induced contractile differentiation of vascular smooth muscle: sensitivity to actin polymerization inhibitors Am J Physiol Cell Physiol, June 1, 2003; 284(6): C1387 - C1396. [Abstract] [Full Text] [PDF]