SPECIAL TOPICS
Prologue: vascular myogenic mechanisms

¹ Department of Obstetrics and Gynecology and ² Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont 05405-0001

	ARTICLE

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TO RESPOND TO FLUCTUATIONS in blood pressure and maintain normal organ blood flow, arteries and arterioles must be able to constrict to increases and dilate to decreases in pressure. The bidirectional nature of this mechanism, in turn, requires the presence of a basal vascular tone from which either further narrowing or dilation may occur. Although other influences (nerves, metabolites, and endothelial factors) may modify the amount of tone present in a particular vessel at any one time, these are superimposed on a more fundamental, myogenic tone, which is defined as "a maintained basal state of contraction which arises within a muscle, without involvement of ... external factors." (9).

This year commemorates the 100th anniversary of the publication of Sir William Baylis' classic 1902 paper (1), which first described the vascular myogenic response, a physiological phenomenon that is integral to the control of basal vascular tone, peripheral resistance, blood pressure, and blood flow autoregulation. The primary stimulus for myogenic activity is the stretch imposed on the vascular wall by intravascular pressure, and its transduction into the production of active force by vascular smooth muscle involves a complex array of mechanisms that involve integrins and ion channels, enzyme translocation and activation, and changes in cytoskeletal structure.

The 18 papers that appear in this Special Topic issue provide a picture of the current state of knowledge on various mechanisms involved in the physiological regulation of myogenic tone as well as how myogenic tone may contribute to, or be influenced by, certain pathological states. These papers fall into three general categories addressing 1) intrinsic ionic and enzymatic regulatory mechanisms controlling myogenic tone, 2) regulatory factors and influences extrinsic to the vascular smooth muscle cell that affect myogenic tone, and 3) influences of both physiological (e.g., pregnancy) and pathological (e.g., cardiomyopathy and subarachnoid hemorrhage) states on myogenic tone.

Papers in the first category consider some of the fundamental mechanisms by which myogenic tone is regulated. Osol and colleagues (15) present a comprehensive model of myogenic tone that summarizes some of the key factors involved in the various phases of intrinsic vascular reactivity generated by changes in intravascular pressure. An important element related to control of myogenic tone appears to be the tendency of myogenically active arteries to maintain a fairly constant level of media stress, as reported by Brekke et al. (2). Two cellular mechanisms and related signaling pathways play key roles in the process by which changes in intravascular pressure alter vascular tone. One mechanism is associated with pressure-induced smooth muscle membrane depolarization, which opens L-type calcium channels, and leads to calcium influx and an elevation in cytosolic calcium. The calcium, in turn, activates calmodulin and myosin light chain (MLC) kinase (MLCK), leading to enhanced MLC phosphorylation and smooth muscle contraction. In this regard, Jarajapu and Knot (8) demonstrate that signaling initiated by phospholipase C is closely associated with the mechanism of pressure-induced depolarization. In a related paper, Slish et al. (18) show the key role of cation channels as mediators of pressure-induced depolarization and demonstrate that protein kinase C (PKC) is centrally involved in modulating the activity of these cation currents. In some arteries, other channels may help regulate calcium entry and calcium handling associated with myogenic tone. VanBavel et al. (19) provide evidence suggesting a role for T-type calcium channels in controlling skeletal muscle arteriolar myogenic tone. Lagaud and colleagues (12) demonstrate that gap junctions play a significant role in maintenance and modulation of pressure-induced changes in smooth muscle membrane potential. There are also more subtle, spatial aspects of calcium signaling that may be important. For example, Heppner et al. (6) demonstrate that changes in smooth muscle cellular pH cause dramatic shifts in the pattern of intracellular calcium signaling from calcium spark events to predominantly calcium waves. These novel patterns of calcium signaling will uniquely influence myogenic behavior. A second general mechanism of pressure-induced vasoconstriction involves changes in the sensitivity of various signaling pathways to calcium, typically leading to enhanced MLCK activity under conditions of steady or even diminished intracellular [Ca²⁺]. This type of signaling involves several important cellular enzyme systems. For example, Massett et al. (14) provide evidence for important roles of both PKC and mitogen-activated protein kinases in the regulation of myogenic tone. Schubert and colleagues (17) show that the RhoA/Rho kinase signaling pathway is involved in the calcium sensitization process associated with myogenic tone. Lagaud et al. (11) demonstrate that myogenic tone can develop independently of changes in membrane potential, apparently also related to alterations in calcium sensitivity of the contractile process.

Myogenic behavior can also be modulated by a variety of extrinsic factors; alternatively, the level of myogenic tone may influence how the vasculature responds to certain extrinsic stimuli. Some of these issues are considered in the second group of papers of this Special Topic on myogenic tone. Earley and Walker (4) show that chronic hypoxia can inhibit the myogenic response via endothelium-dependent pathways. Koller and Zsolt (10) provide evidence that the level of myogenic tone can influence the magnitude and duration of skeletal muscle arteriolar dilation (reactive hyperemia) induced by a period of flow occlusion. Liu and colleagues (13) describe the interactions between myogenic tone and hypoxia-induced dilator responses in the cerebral circulation. Coulson et al. (3) report that myogenic tone has substantial effects on the biomechanical properties (stiffness and elastic modulus) of cerebral arteries isolated from control versus ischemic tissues.

Both physiological (pregnancy) and pathological states (e.g., ischemia, subarachnoid hemorrhage, and cardiomyopathy) can significantly impact cardiovascular function, and evidence is presented in the third group of papers indicating that myogenic behavior can be affected substantially by these conditions. Frisbee et al. (5) show that oxidant stress significantly increases myogenic tone in a rat model of obesity. Veerareddy and colleagues (20) demonstrate that part of the enormous vascular adaptation that occurs during pregnancy may be explained by alterations in myogenic mechanisms. Two other papers in this group provide evidence for altered myogenic mechanisms in diseased states. Petersen et al. (16) describe substantial alterations in the myogenic activity of coronary arteries in a model of hypertrophic cardiomyopathy, as have Ishiguro et al. (7) in cerebral arteries following subarachnoid hemorrhage.

A number of the papers in this issue were presented at the 2002 Myogenic Centennial conference held in Stowe, Vermont, on June 12-15, 2002. In addition to the Guest Editors, the organizers included Drs. Marilyn Cipolla and Mark Nelson, who chaired a workshop aimed at identifying areas of current controversy. The consensus was that we have learned much about the mechanisms by which myogenic responses are effected but relatively little about the upstream events, specifically those that involve mechanotransmission of forces within the vascular wall and their mechanotransduction into the events discussed above.

The Centennial meeting concluded with a second workshop on future directions for research, which raised some provocative questions, for example:

• Why do some vessels develop tone, whereas others do not?
• Are there phenotypic differences between cells within the vascular wall; specifically, does a subpopulation of pacemaker or sensor cells exist and influence adjacent cells in a paracrine manner?
• What is the nature of coupling and signaling between cells (how are myogenic responses integrated)?
• What structures are involved in the sensing and transmission of forces from the matrix to the vascular smooth muscle cell and from cell to cell?
• What are the spatial relationships between signal transduction events and cellular structures (e.g., cytoskeleton as a scaffold for kinases, translocation events, and linkage of channels with regulatory processes)?
• What are the contributions of thick versus thin filament regulatory pathways, including modulation of MLCK activity and calcium sensitivity?
• How and why are myogenic mechanisms altered in pathological states such as hypertension and diabetes?
• What is the influence of aging on the myogenic response?

Clearly, there is much left to learn about vascular myogenic behavior, from its in vivo role in the control of organ blood flow and total peripheral resistance at one extreme to the molecular genetics that underlie its expression and regulation at the other. This is the challenge that faces us in the years ahead, and it is our hope that the papers included in this Special Topic capture the current state of our knowledge of this field and provide a useful substrate for future investigations and collaborations.

	FOOTNOTES

 This article belongs to a collection of papers accepted in response to the Editor's special call for papers entitled "Mechanisms of vascular myogenic tone."

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpheart.00746.2002

	REFERENCES

TOP ARTICLE REFERENCES

1.   Baylis, WM. On the local reactions of the arterial wall to changes of internal pressure. J Physiol 28: 220-231, 1902.

2.   Brekke, JF, Gokina NI, and Osol G. Vascular smooth muscle stress as a determinant of cerebral artery myogenic tone. Am J Physiol Heart Circ Physiol 283: H2210-H2216, 2002[Abstract/Free Full Text].

3.   Coulson, RJ, Chesler NC, Vitullo L, and Cipolla M. Effects of ischemia and myogenic activity on the active and passive mechanical properties of rat cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2268-H2275, 2002[Abstract/Free Full Text].

4.   Earley, S, and Walker BR. Endothelium-dependent blunting of myogenic responsiveness after chronic hypoxia. Am J Physiol Heart Circ Physiol 283: H2202-H2209, 2002[Abstract/Free Full Text].

5.   Frisbee, JC, Maier KG, and Stepp DW. Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats. Am J Physiol Heart Circ Physiol 283: H2160-H2168, 2002[Abstract/Free Full Text].

6.   Heppner, TJ, Bonev AD, Santana LF, and Nelson MT. Alkaline pH shifts Ca²⁺ sparks to Ca²⁺ waves in smooth muscle cells of pressurized cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2169-H2176, 2002[Abstract/Free Full Text].

7.   Ishiguro, M, Puryear CB, Bisson E, Saundry CM, Nathan DJ, Tranmer BI, and Wellman GC. Enhanced myogenic tone in cerebral arteries from a rabbit model of subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol 283: H2217-H2225, 2002[Abstract/Free Full Text].

8.   Jarajapu Yagna, PR, and Knot HJ. Role of phospholipase C in the development of myogenic tone in rat posterior cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2234-H2238, 2002[Abstract/Free Full Text].

9.   Johansson, B. Myogenic tone and reactivity: definitions based on muscle physiology. J Hypertens Suppl 7: S5-S8, 1989[Medline].

10.   Koller, A, and Zsolt B. On the role of mechanosensitive mechanisms eliciting reactive hyperemia. Am J Physiol Heart Circ Physiol 283: H2250-H2259, 2002[Abstract/Free Full Text].

11.   Lagaud, G, Gaudereault N, Moore EDW, van Breemen C, and Laher I. Pressure-dependent myogenic constriction of cerebral arteries occurs independently of voltage-dependent activation. Am J Physiol Heart Circ Physiol 283: H2187-H2195, 2002[Abstract/Free Full Text].

12.   Lagaud, G, Karicheti V, van Breemen C, Christ GJ, and Laher I. Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2177-H2186, 2002[Abstract/Free Full Text].

13.   Liu, Y, Harder DR, and Lombard JH. Interaction of myogenic mechanisms and hypoxic dilation in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2276-H2281, 2002[Abstract/Free Full Text].

14.   Massett, MP, Ungvari Z, Csiszar A, Kaley G, and Koller A. Differential role of PKC and MAP kinases in arteriolar constrictions to pressure and agonists. Am J Physiol Heart Circ Physiol 283: H2282-H2287, 2002[Abstract/Free Full Text].

15.   Osol, G, Brekke JF, McElroy-Yaggy K, and Gokina NI. Myogenic tone, reactivity and forced dilatation: three-phase model of in vitro arterial myogenic behavior. Am J Physiol Heart Circ Physiol 283: H2260-H2267, 2002[Abstract/Free Full Text].

16.   Petersen, HH, Choy J, Stauffer B, Moien-Afshari FM, Aalkjaer C, Leinwand L, McManus BM, and Laher I. Coronary artery myogenic response in a genetic model of hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 283: H2244-H2249, 2002[Abstract/Free Full Text].

17.   Schubert, R, Kalentchuk VU, and Krien U. Rho-kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity. Am J Physiol Heart Circ Physiol 283: H2288-H2295, 2002[Abstract/Free Full Text].

18.   Slish, DF, Welsh DG, and Brayden JE. Diaclyglycerol and protein kinase C activate cation channels involved in myogenic tone. Am J Physiol Heart Circ Physiol 283: H2196-H2201, 2002[Abstract/Free Full Text].

19.   VanBavel, E, Sorop O, Andreason D, Pfaffendorf M, and Jensen BL. Role of T-type calcium channels in myogenic tone of skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol 283: H2239-H2243, 2002[Abstract/Free Full Text].

20.   Veerareddy, S, Cooke CM, Baker PN, and Davidge ST. Vascular adaptations to pregnancy in mice: effects on myogenic tone. Am J Physiol Heart Circ Physiol 283: H2226-H2233, 2002[Abstract/Free Full Text].