Effects of arterial wall stress on vasomotion

Smooth muscle and endothelial cells in the arterial wall are exposed to mechanical stress. Indeed blood flow induces intraluminal pressure variations and shear stress. An increase in pressure may induce a vessel contraction, a phenomenon known as the myogenic response. Many muscular vessels present vasomotion, i.e., rhythmic diameter oscillations caused by synchronous cytosolic calcium oscillations of the smooth muscle cells. Vasomotion has been shown to be modulated by pressure changes. To get a better understanding of the effect of stress and in particular pressure on vasomotion, we propose a model of a blood vessel describing the calcium dynamics in a coupled population of smooth muscle cells and endothelial cells and the consequent vessel diameter variations. We show that a rise in pressure increases the calcium concentration. This may either induce or abolish vasomotion, or increase its frequency depending on the initial conditions. In our model the myogenic response is less pronounced for large arteries than for small arteries and occurs at higher values of pressure if the wall thickness is increased. Our results are in agreement with experimental observations concerning a broad range of vessels.     

Diacylglycerol and protein kinase C activate cation channels involved in myogenic tone

The smooth muscle cells of resistance arteries depolarize and contract when intravascular pressure is elevated. This is a central characteristic of myogenic tone, which plays an important role in regulation of blood flow in many vascular beds. Pressure-induced vascular smooth muscle depolarization depends in part on the activation of cation channels. Here, we show that activation of these smooth muscle cation channels and pressure-induced depolarization are mediated by protein kinase C in cerebral resistance arteries. Diacylglycerol, phorbol myristate acetate, and cell swelling activate a cation current that we have previously shown is mediated by transient receptor potential channels. These currents, as well as the smooth muscle cell depolarizations of intact arteries induced by diacylglycerol, phorbol ester, and elevation of intravascular pressure, are nearly eliminated by protein kinase C inhibitors. These results suggest a major mechanism of myogenic tone involves mechanotransduction through phospholipase C, diacylglycerol production, and protein kinase C activation, which increase cation channel activity. The associated depolarization activates L-type calcium channels, leading to increased intracellular calcium and vasoconstriction.     

Surrounding tissues affect the passive mechanics of the vessel wall: theory and experiment

The stress and strain in the vessel wall are important determinants of vascular physiology and pathophysiology. Vessels are constrained radially by the surrounding tissue. The hypothesis in this work is that the surrounding tissue takes up a considerable portion of the intravascular pressure and significantly reduces the wall strain and stress. Ten swine of either sex were used to test this hypothesis. An impedance catheter was inserted into the carotid or femoral artery, and after mechanical preconditioning pressure-cross-sectional area relations were obtained with the surrounding tissue intact and dissected away (untethered), respectively. The radial constraint of the surrounding tissue was quantified as an effective perivascular pressure on the outer surface of the vessel, which was estimated as 50% or more of the intravascular pressure. For carotid arteries at pressure of 100 mmHg, the circumferential wall stretch ratio in the intact state was approximately 20% lower than in the untethered state and the average circumferential stress was reduced by approximately 70%. For femoral arteries, the reductions were approximately 15% and 70%, respectively. These experimental data support the proposed hypothesis and suggest that in vitro and in vivo measurements of the mechanical properties of vessels must be interpreted with consideration of the constraint of the surrounding tissue.     

Changes of opening angle in hypertensive and hypotensive arteries in 3-day organ culture

To study the effect of pressure changes on the opening angle of arteries in organ culture, tubular segments of porcine common carotid arteries were cultured with pulsatile flow perfusion under hypertensive (150+/-20 mmHg), normotensive (100+/-20 mmHg), or hypotensive (30+/-10 mmHg) pressure while maintaining the arteris at a physiological wall shear stress of approximately 15 dyn/cm(2) for up to 3 days. Arteries were then cut into short ring segments by sections perpendicular to the axis and then cut open radially to observe the opening angle in aerated phosphate buffered saline solution (37 degrees C). Norepinephrine (NE, 10 microM), carbacol (CCh, 100 microM), and sodium nitroprusside (SNP, 10 microM) were added after the radial cut at 30, 20, and 30 min intervals, the opening angles were measured, respectively. Results show that hypertensive arteries developed a significantly larger opening angle than normotensive and hypotensive arteries, associated with a significant increase in cell proliferation. In addition, with smooth muscle contraction activated by NE, the opening angle decreases significantly in hypertensive arteries but has little change in hypotensive and normotensive arteries, indicating an enhancement of smooth muscle contraction on the lumen side of the hypertensive arterial wall. In comparison, hypotensive pressure has little effect on arterial opening angle and cell proliferation.     

Biomechanical adaptation of porcine carotid vascular smooth muscle to hypo and hypertension in vitro

Previous research in arterial remodeling in response to changes in blood pressure seldom included both hyper- and hypotension. To compare the effects of low and high pressure on arterial remodeling and vascular smooth muscle tone and performance, we have utilized an in vitro model. Porcine carotid arteries were cultured for 3 days at 30 and 170mmHg and compared to controls cultured at 100mmHg for 1 and 3 days. On the first and last day of culture, pressure-diameter and pressure-wall thickness curves were measured under normal smooth muscle tone using a high-resolution ultrasonic device. Last-day experiments included measurements where vascular smooth muscle was contracted or totally relaxed. From the data wall cross-sectional area, Hudetz elastic modulus and a contraction index related to the diameter reduction under normal smooth muscle tone were calculated. We found that although wall cross-sectional area (indicating wall mass) did not change much, Hudetz elastic modulus was significantly reduced in the 3-day hypotension group. Inspection of the wall contraction index suggests that this is due to a reduction in the vascular smooth muscle tone. Further, the peak of contraction index was found to be shifted to higher pressures in the 3-day 170mmHg group. We conclude that vascular smooth muscle performance adapts to both hypo- and hypertension at short time scales and can alter the biomechanics of the vascular wall in vitro.     

Effect of age on mechanical properties of rat mesenteric small arteries

With aging, large arteries become stiffer and systolic blood pressure consequently increases. Less is known, however, about the age-related change in mechanics of small resistance arteries. The aim of this study was to determine whether aging plays a role in the stiffening of the small mesenteric arteries of rats. Intra-arterial systolic, diastolic, mean and pulse pressures were measured in male Wistar rats aged 2, 4, 15 and 26 months. The passive mechanical properties of the wall of isolated perfused and pressurized arterial segments of mesenteric small arteries were also investigated. Intra-arterial systolic, diastolic and mean blood pressures tended to decrease with age and were significantly lower in the oldest rats (26-month-old group). Pulse pressure was significantly higher in the 15- and 26-month-old groups than in the two younger groups. Under isobaric conditions, increasing age is associated with an outward hypertrophic remodeling of the mesenteric arteries. Under relaxed conditions, incremental distensibility in response to increasing intravascular pressure did not change with aging. As a function of strain (under isometric conditions), stress shifted to the left as age increased, indicating an age-related vascular stiffening. Under isobaric conditions or in relation to wall stress, the elastic modulus was greater in the adult 15-month-old rats than in the younger rats. These findings suggest that distensibility seems to be preserved with aging, despite stiffness of the wall components, probably by arterial wall geometric adaptation, which limits the pulse pressure damage. It is interesting to note that elastic modulus in mesenteric arteries from the oldest rats (26-month-old), examined in relation to wall stress and intravascular pressure, did not differ from that of the youngest rats, thus suggesting that elasticity of wall components had been restored.     

Arteriolar vascular smooth muscle cells: mechanotransducers in a complex environment

Contraction of small artery (diameters typically less than 250 μm) vascular smooth muscle cells (VSMCs) plays a critical role in local control of blood flow and arterial pressure through its affect on vascular caliber. Specifically, contraction of small arteries in response to increased intraluminal pressure is referred to as the myogenic response and represents an important role for mechanotransduction. Critical questions remain as to how changes in pressure are sensed by VSMCs and transduced across the cell membrane to tune the contractile state of the cell. Recent studies suggest a pivotal role for interactions between VSMCs and extracellular matrix (ECM) proteins. Thus, pressure-induced deformation of ECM proteins and their cell surface receptors (for example, integrins) may initiate contraction and cytoskeletal remodeling through modulation of ion channels, membrane depolarization, increased intracellular Ca(2+) and actomyosin crossbridge cycling. Importantly, it is argued that the contractile properties of small artery VSMCs reflect an intimate and integrated interaction with their extracellular environment and the three-dimensional structure of the vessel wall.     

A constitutive formulation of arterial mechanics including vascular smooth muscle tone

A pseudo-strain energy function (pseudo-SEF) describing the biomechanical properties of large conduit arteries under the influence of vascular smooth muscle (VSM) tone is proposed. In contrast to previous models that include the effects of smooth muscle contraction through generation of an active stress, in this study we consider the vascular muscle as a structural element whose contribution to load bearing is modulated by the contraction. This novel pseudo-SEF models not only arterial mechanics at maximal VSM contraction but also the myogenic contraction of the VSM in response to local increases in stretch. The proposed pseudo-SEF was verified with experimentally obtained pressure-radius curves and zero-stress state configurations from rat carotid arteries displaying distinct differences in VSM tone: arteries from normotensive rats displaying minimal VSM tone and arteries from hypertensive rats exhibiting significant VSM tone. The pressure-radius curves were measured in three different VSM states: fully relaxed, maximally contracted, and normal VSM tone. The model fitted the experimental data very well (r2 > 0.99) in both the normo- and hypertensive groups for all three states of VSM activation. The pseudo-SEF was used to illustrate the localized reduction of circumferential stress in the arterial wall due to normal VSM tone, suggesting that the proposed pseudo-SEF can be of general utility for describing stress distribution not only under passive VSM conditions, as most SEFs proposed so far, but also under physiological and pathological conditions with varying levels of VSM tone.     

Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries

Mechanisms that underlie autoregulation in the newborn vasculature are unclear. Here we tested the hypothesis that in newborn porcine cerebral arteries intravascular pressure elevates wall tension, leading to an increase in intracellular calcium concentration ([Ca2+]i) and a constriction that is opposed by pressure-induced K+ channel activation. Incremental step (20 mmHg) elevations in intravascular pressure between 10 and 90 mmHg induced an immediate transient elevation in arterial wall [Ca2+]i and a short-lived constriction that was followed by a smaller steady-state [Ca2+]i elevation and sustained constriction. Pressures between 10 and 90 mmHg increased steady-state arterial wall [Ca2+]i between approximately 142 and 299 nM and myogenic (defined as passive-active) tension between 25 and 437 dyn/cm. The relationship between pressure and myogenic tension was strongly Ca2+ dependent until forced dilation. At low pressure, 60 mM K+ induced a steady-state elevation in arterial wall [Ca2+]i and a constriction. Nimodipine, a voltage-dependent Ca2+ channel blocker, and removal of extracellular Ca2+ similarly dilated arteries at low or high pressures. 4-Aminopyridine, a voltage-dependent K+ (Kv) channel blocker, induced significantly larger constrictions at high pressure, when compared with those at low pressure. Although selective Ca2+-activated K+ (KCa) channel blockers and intracellular Ca2+ release inhibitors induced only small constrictions at low and high pressures, a low concentration of caffeine (1 microM), a ryanodine-sensitive Ca2+ release (RyR) channel activator, increased KCa channel activity and induced dilation. These data suggest that in newborn cerebral arteries, intravascular pressure elevates wall tension, leading to voltage-dependent Ca2+ channel activation, an increase in wall [Ca2+]i and Ca2+-dependent constriction. In addition, pressure strongly activates Kv channels that opposes constriction but only weakly activates KCa channels.     

A logistic-type curve fits pressure-diameter relationship for relaxed and contracted dog renal arteries

In order to describe a possible effect of smooth muscle cell (SMC) activation on arterial wall distensibility, the present study derived a mathematical equation applicable to relaxed and contracted arterial walls. Pressure(P)-diameter(D) relationship of dog renal arteries was investigated in vitro under a cyclic loading and unloading process in the pressure range of 5-180 mmHg. Smooth muscle cells were activated by 10(-5)M norepinephrine. On the basis of the P-D curves obtained with fully contracted arteries, the vessel wall compliance dD/dP was assumed to be given by a second order polynomial of D, (formula; see text) The equation, including three parameters, Dmin, Dmax, and E, is integrated to yield the solution similar to the logistic curve as follows (formula; see text) where M(O) = (Dmax - D(O]/(D(O) - Dmin), and D(O) is the diameter at the point P = O. The constant, E, has the same dimension as the modulus of elasticity. The calculated P-D relationships coincided well with the experimental data for contracted and relaxed arteries. The most significant change due to wall contraction took place in the magnitude of M. This result, therefore, suggests that the parameter M is a good index of the degree of SMC contraction.     

Extracellular matrix and the mechanics of large artery development

The large, elastic arteries, as their name suggests, provide elastic distention and recoil during the cardiac cycle in vertebrate animals. The arteries are distended from the pressure of ejecting blood during the active contraction of the left ventricle (LV) during systole and recoil to their original dimensions during relaxation of the LV during diastole. The cyclic distension occurs with minimal energy loss, due to the elastic properties of one of the major structural extracellular matrix (ECM) components, elastin. The maximum distension is limited to prevent damage to the artery by another major ECM component, collagen. The mix of ECM components in the wall largely determines the passive mechanical behavior of the arteries and the subsequent load on the heart during systole. While much research has focused on initial artery formation, there has been less attention on the continuing development of the artery to produce the mature composite wall complete with endothelial cells (ECs), smooth muscle cells (SMCs), and the necessary mix of ECM components for proper cardiovascular function. This review focuses on the physiology of large artery development, including SMC differentiation and ECM production. The effects of hemodynamic forces and ECM deposition on the evolving arterial structure and function are discussed. Human diseases and mouse models with genetic mutations in ECM proteins that affect large artery development are summarized. A review of constitutive models and growth and remodeling theories is presented, along with future directions to improve understanding of ECM and the mechanics of large artery development.     

Local longitudinal muscle shortening of the human esophagus from high-frequency ultrasonography

We analyzed local longitudinal shortening by combining concurrent ultrasonography and manometry with basic principles of mechanics. We applied the law of mass conservation to quantify local axial shortening of the esophageal wall from ultrasonically measured cross-sectional area concurrently with measured intraluminal pressure, from which correlations between local contraction of longitudinal and circular muscle are inferred. Two clear phases of local longitudinal shortening were observed during bolus transport. During luminal filling by bolus fluid, the muscle layer distends and the muscle thickness decreases in the absence of circular or longitudinal muscle contraction. This is followed by local contraction, first in longitudinal muscle, then in circular muscle. Maximal longitudinal shortening occurs nearly coincidently with peak intraluminal pressure. Longitudinal muscle contraction begins before and ends after circular muscle contraction. Larger longitudinal shortening is correlated with higher pressure amplitude, suggesting that circumferential contractile forces are enhanced by longitudinal muscle shortening. We conclude that a peristaltic wave of longitudinal muscle contraction envelops the wave of circular muscle contraction as it passes through the middle esophagus, with peak longitudinal contraction aligned with peak circular muscular contraction. Our results suggest that the coordination of the two waves may be a physiological response to the mechanical influence of longitudinal shortening, which increases contractile force while reducing average muscle fiber tension by increasing circular muscle fiber density locally near the bolus tail.     

Effect of acute ischaemia on active and passive large deformation mechanics of canine carotid arteries

Large deformation mechanical properties of dog carotid arteries excised following 1 hour of ischaemia and 1 hour of reperfusion were compared to those of contralaterial normal arteries in vitro. Vascular smooth muscle was invariably activated by 0.5 microgram/ml noradrenaline. Relative reduction in the diameter of postischaemia arteries following noradrenaline administration was twice as large (max.: 13.2 +/- 2.0%) as that of normal controls (max.: 5.7 +/- 1.5%) in the pressure range of 0--220 mmHg. If the smooth muscle was totally relaxed there were no differences between the geometrical (wall-thickness, radius) and mechanical properties (stress, incremental elastic modulus, incremental distensibility, strain-energy density) of the arteries in the two series. It is concluded that the increased reactivity of postischaemic arteries is not caused by changes in geometric or mechanical properties of their passive wall elements.     

Impedance of the chest wall during sustained respiratory muscle contraction

We measured total chest wall impedance (Zw), "pathway impedances" of the rib cage (Zrcpath), and diaphragm-abdomen (Zd-apath), and impedance of the belly wall including abdominal contents (Zbw+) in five subjects during sustained expiratory (change in average pleural pressure [Ppl] from relaxation = 10 and 20 cmH2O) and inspiratory (change in Ppl = -10 and -20 cmH2O) muscle contraction, using forced oscillatory techniques (0.5-4 Hz) we have previously reported for relaxation (J. Appl. Physiol. 66: 350-359, 1989). Chest wall configuration and mean lung volume were kept constant. Zw, Zrcpath, Zd-apath, and Zbw+ all increased greatly at each frequency during expiratory muscle contraction; increases were proportional to effort. Zw, Zrcpath, and Zd-apath increased greatly during inspiratory muscle contraction, but Zbw+ did not. Resistances and elastances calculated from each of the impedances showed the same changes during muscle contraction as the corresponding impedances. Each of the resistances decreased as frequency increased, independent of effort; elastances generally increased with frequency. These frequency dependencies were similar to those measured in relaxed or tetanized isolated muscle during sinusoidal stretching (P.M. Rack, J. Physiol. Lond. 183: 1-14, 1966). We conclude that during respiratory muscle contraction 1) chest wall impedance increases, 2) changes in regional chest wall impedances can be somewhat independent, depending on which muscles contract, and 3) increases in chest wall impedance are due, at least in part, to changes in the passive properties of the muscles themselves.     

Temporal relationships between wall motion, intraluminal pressure, and flow in the isolated rabbit small intestine

Intraluminal manometry is a tool commonly used to record motility in the human digestive tract. The recorded signal results from a combination of factors, including the hydrodynamic pressure transmitted through the intestinal contents due to contraction of the gut wall and the force of the gut wall acting on the sensors in regions of a luminal occlusion. However, the actual relationships between small bowel wall contraction, the measured intraluminal pressure, and the resultant flow have not been directly addressed. Video recording and high-resolution fiber-optic manometry were used to create spatiotemporal video maps of diameter and intraluminal pressure from isolated segments of rabbit small intestine. In the unstimulated gut, longitudinal muscle contractions were the only detectable motor pattern; circular muscle contractions were elicited by distension or erythromycin (1 μM). Longitudinal muscle contractions were not lumen-occlusive, although they caused measurable low-amplitude changes in pressure. Localized nonpropagating circular muscle contractions caused small localized, nonpropagating peaks of intraluminal pressure. Propagating contractions of circular muscle evoked larger, propagating pressure changes that were associated with outflow. Propagating circular muscle contractions often caused dilation of aboral receiving segments, corresponding to "common cavities"; these were propulsive, despite their low intraluminal pressure. The highest-amplitude pressure events were caused by lumen-occlusive circular muscle contractions that squeezed directly against the catheter. These data allow us to define the complex relationships between wall motion, intraluminal pressure, and flow. A strong correlation between circular and longitudinal muscle contraction and intraluminal pressure was demonstrated. Common-cavity pressure events, caused by propulsion of content by circular muscle contractions into a receptive segment, were often of low amplitude but were highly propulsive. Studies of wall motion in isolated preparations, combined with manometry, can assist in interpretation of pressure recordings in vivo.     

Caveolin-1 abolishment attenuates the myogenic response in murine cerebral arteries

Intravascular pressure-induced vasoconstriction (the "myogenic response") is intrinsic to smooth muscle cells, but mechanisms that underlie this response are unresolved. Here we investigated the physiological function of arterial smooth muscle cell caveolae in mediating the myogenic response. Since caveolin-1 (cav-1) ablation abolishes caveolae formation in arterial smooth muscle cells, myogenic mechanisms were compared in cerebral arteries from control (cav-1(+/+)) and cav-1-deficient (cav-1(-/-)) mice. At low intravascular pressure (10 mmHg), wall membrane potential, intracellular calcium concentration ([Ca(2+)](i)), and myogenic tone were similar in cav-1(+/+) and cav-1(-/-) arteries. In contrast, pressure elevations to between 30 and 70 mmHg induced a smaller depolarization, [Ca(2+)](i) elevation, and myogenic response in cav-1(-/-) arteries. Depolarization induced by 60 mM K(+) also produced an attenuated [Ca(2+)](i) elevation and constriction in cav-1(-/-) arteries, whereas extracellular Ca(2+) removal and diltiazem, an L-type Ca(2+) channel blocker, similarly dilated cav-1(+/+) and cav-1(-/-) arteries. N(omega)-nitro-l-arginine, an nitric oxide synthase inhibitor, did not restore myogenic tone in cav-1(-/-) arteries. Iberiotoxin, a selective Ca(2+)-activated K(+) (K(Ca)) channel blocker, induced a similar depolarization and constriction in pressurized cav-1(+/+) and cav-1(-/-) arteries. Since pressurized cav-1(-/-) arteries are more hyperpolarized and this effect would reduce K(Ca) current, these data suggest that cav-1 ablation leads to functional K(Ca) channel activation, an effect that should contribute to the attenuated myogenic constriction. In summary, data indicate that cav-1 ablation reduces pressure-induced depolarization and depolarization-induced Ca(2+) influx, and these effects combine to produce a diminished arterial wall [Ca(2+)](i) elevation and constriction.     

Calcium sensitivity of vasospastic basilar artery after experimental subarachnoid hemorrhage

Arteries that develop vasospasm after subarachnoid hemorrhage (SAH) may have altered contractility and compliance. Whether these changes are due to alterations in the smooth muscle cells or the arterial wall extracellular matrix is unknown. This study elucidated the location of such changes and determined the calcium sensitivity of vasospastic arteries. Dogs were placed under general anesthesia and underwent creation of SAH using the double-hemorrhage model. Vasospasm was assessed by angiography performed before and 4, 7, or 21 days after SAH. Basilar arteries were excised from SAH or control dogs (n = 8-52 arterial rings from 2-9 dogs per measurement) and studied under isometric tension in vitro before and after permeabilization of smooth muscle with alpha-toxin. Endothelium was removed from all arteries. Vasospastic arteries demonstrated significantly reduced contractility to KCl with a shift in the EC(50) toward reduced sensitivity to KCl 4 and 7 days after SAH (P < 0.05, ANOVA). There was reduced compliance that persisted after permeabilization (P < 0.05, ANOVA). Calcium sensitivity was decreased during vasospasm 4 and 7 days after SAH, as assessed in permeabilized arteries and in those contracted with BAY K 8644 in the presence of different concentrations of extracellular calcium (P < 0.05, ANOVA). Depolymerization of actin with cytochalasin D abolished contractions to KCl but failed to alter arterial compliance. In conclusion, it is shown for the first time that calcium sensitivity is decreased during vasospasm after SAH in dogs, suggesting that other mechanisms are involved in maintaining the contraction. Reduced compliance seems to be due to an alteration in the arterial wall extracellullar matrix rather than the smooth muscle cells themselves because it cannot be alleviated by depolymerization of smooth muscle actin.     

Elastic tissue and smooth muscle volume in elastic and muscular type arteries in the dog

1. Relative elastic tissue and smooth muscle volumes were determined by a stereological point-counting method in arteries with a progressively diminishing diameter, from the aorta towards the periphery. 2. The volume relationship between the smooth muscle cell and its nucleus was determined by the same method. Mean nuclear volume amounted to 6.9% of total smooth muscle cell volume. 3. Relative elastic tissue volume fell from the aorta towards the peripheral arteries, from 22.6% in the ascending aorta to 4--6% in the smallest arteries examined. 4. Relative smooth muscle volume was practically the same and differences between the individual values in the vast majority of arteries examined were non-significant. Total smooth muscle volume, calculated from the volume of the smooth muscle cell nuclei, varied mostly from 45 to 55%. 5. It can be concluded from these results that the ability of small and medium muscular type arteries to change their diameter actively by muscular contraction (as against elastic type arteries, in which this ability is less expressed) is facilitated not only by the organization of the structural components of the arterial wall, but also by the lower elastic tissue volume, which is compensated by the volume of the other passive components of the vascular wall, while relative smooth muscle volume remains the same.