Microalbuminuria in Type 2 diabetes indicates impaired microvascular vasomotion and perfusion

Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aims were to assess the relationship of vasomotion to perfusion in the cutaneous microcirculation of diabetic patients, to determine the influence on it of endothelium-dependent and nonendothelium-dependent vasodilatory stimuli, and to assess the relationship to perfusion and vasomotion of various biochemical markers of vascular function (HbA1c, LDL- and HDL-cholesterol, triglycerides, insulin resistance, high sensitive C-reactive protein, L- and E-selectin, soluble ICAM, von Willebrand factor) and microalbuminuria. Perfusion and vasomotion (spectral density at low and very low frequencies) were measured by laser-Doppler flowmetry after local heat and iontophoresis of ACh and sodium nitroprusside. Perfusion responses to all stimuli were impaired in patients with Type 2 diabetes (heat: F = 28.0, P < 0.001; ACh: F = 7.11, P = 0.003; sodium nitroprusside: F = 4.0, P = 0.028). Responses to endothelium-dependent stimuli were further impaired in microalbuminuric patients (heat: P = 0.035; ACh: P = 0.034). Vasomotion responses at low frequencies after endothelium-dependent stimuli were impaired in diabetic patients compared with that shown in controls (heat: F = 5.62, P = 0.002; ACh: F = 4.32, P = 0.015). Multivariate modeling showed microalbuminuria to be the only consistent predictor of perfusion and vasomotion responses. The results suggest that microalbuminuria in Type 2 diabetes reflects a generalized disturbance of microvascular function related to endothelium-dependent mechanisms.     

Modulation of vasomotion in resistance arteries of JCR:LA-cp rats: a model of insulin resistance.

Obesity and insulin resistance are strongly associated with an increased risk of vascular disease. Vasomotion is the cyclic variation in the diameter of arteries and is a general feature of the vasculature that may have important physiological consequences. We tested the hypothesis that obesity - insulin resistance is associated with abnormal vasomotion by comparing obese, insulin-resistant JCR:LA-cp rats, known to develop vasculopathy, atherosclerosis, and ischemic lesions of the heart, with lean insulin-sensitive animals from the same strain. Vasomotion was assessed using isolated mesenteric arteries on a myograph system after preconstriction to 50% of maximal constriction with norepinephrine. The amplitude of vasomotion was enhanced by the presence of meclofenamate, a prostaglandin H synthase inhibitor, and was diminished by N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Removal of the endothelium essentially abolished vasomotion, and meclofenamate had no effect on de-endothelialized arteries. Frequency was not altered by either L-NAME or meclofenamate. Although pharmacological inhibition of nitric oxide and eicosanoid production clearly altered vasomotion, there was no difference in the amplitude or frequency of vasomotion in arteries from obese rats compared with lean rats. These results indicate that the endothelium plays a central role in modulating vasomotion, involving both enhancing and inhibiting effects, and that vasomotion is similar between obese, insulin-resistant and lean, insulin-sensitive rats.     

The role of the liver in lipid metabolism during cold acclimation in non-hibernator rodents

Cold exposure increases the demand for energy substrates. Cold acclimation of rats led to a 3-fold increase in fatty acid (FA) beta-oxidation (P<0.01) for ex vivo livers perfused at 37 degrees C. This increase was preserved following perfusion at 25 degrees C (P<0.001). In vitro measurement of absolute rates of hepatic beta-oxidation revealed no significant difference following cold acclimation, implying changes in fatty acid flux through beta-oxidation rather than increased oxidation capacity. Total FA uptake was increased one-third following perfusion at 25 degrees C (P<0.001) and cold acclimation (P<0.05) and cold acclimation led to diversion of tissue FA from storage to beta-oxidation (P<0.01). In separate experiments, in vivo hepatic lipogenesis rates for saponifiable lipids doubled (P<0.01) and cholesterol synthesis increased one-third (P<0.001). Taken together these data suggest the oxidation and synthesis of lipids occur simultaneously in hepatic tissue possibly to increase prevailing tissue FA concentrations and to generate heat through increased metabolic flux rates.     

Antiphase oscillations of endothelium and smooth muscle [Ca2+]i in vasomotion of rat mesenteric small arteries

The mechanisms leading to vasomotion in the presence of noradrenaline and inhibitors of the sarcoplasmic/endoplasmic reticulum calcium ATPase were investigated in isolated rat mesenteric small arteries. Isobaric diameter and isometric force were measured together with membrane potential in endothelial cells and smooth muscle cells (SMC). Calcium in the endothelial cells and SMC was imaged with confocal microscopy. In the presence of noradrenaline and cyclopiazonic acid, ryanodine-insensitive oscillations in tone were produced. The frequency was about 1 min(-1) and amplitude about 70% of the maximal tone. The amplitude was reduced by indomethacin and increased with L-NAME. Vasomotion was inhibited by nifedipine and by 40 mM potassium. The frequency was increased and amplitude decreased by removal of the endothelium and by application of charybdotoxin and apamin. The vasomotion was associated with in-phase oscillations of membrane potential in endothelial cells and SMC and oscillations of [Ca2+]i that were in near anti-phase. We suggest a working model for the generation of oscillation based on a membrane oscillator where ion channels in both endothelial cells and SMC interact via a current running between the two cell types through myoendothelial gap junctions, which sets up a near anti-phase oscillation of [Ca2+]i in the two cell types.     

Role of membrane potential in vasomotion of isolated pressurized rat arteries

Vasomotion, the phenomenon of vessel diameter oscillation, regulates blood flow and resistance. The main parameters implicated in vasomotion are particularly the membrane potential and the cytosolic free calcium in smooth muscle cells. In this study, these parameters were measured in rat perfused-pressurized mesenteric artery segments. The application of norepinephrine (NE) caused rhythmic diameter contractions and membrane potential oscillations (amplitude; 5.3 +/- 0.3 mV, frequency; 0.09 +/- 0.01 Hz). Verapamil (1 microM) abolished this vasomotion. During vasomotion, 10(-5) M ouabain (Na(+)-K(+) ATPase inhibitor) decreased the amplitude of the electrical oscillations but not their frequency (amplitude; 3.7 +/- 0.3 mV, frequency; 0.08 +/- 0.002 Hz). Although a high concentration of ouabain (10(-3) M) (which exhibits non-specific effects) abolished both electrical membrane potential oscillations and vasomotion, we conclude that the Na+-K+ ATPase could not be implicated in the generation of the membrane potential oscillations. We conclude that in rat perfused-pressurized mesenteric artery, the slow wave membrane type of potential oscillation by rhythmically gating voltage-dependent calcium channels, is responsible for the oscillation of intracellular calcium and thus vasomotion.     

Fluctuations in rat testicular interstitial oxygen tensions are linked to testicular vasomotion: persistence after repair of torsion

Testicular microvascular blood flow is known to exhibit vasomotion, which has been shown to be significantly altered in the short term following the repair of testicular torsion. This loss of vasomotion may ultimately be responsible for the loss of spermatogenesis observed after testicular torsion in rats. In the present study, testicular vasomotion and interstitial oxygen tensions were simultaneously measured prior to, during, and at various time points after repair of testicular torsion in the rat. Testicular torsion was induced by a 720 degrees rotation of the testis for 1 h. Laser-Doppler flowmetry and an oxygen electrode were used to simultaneously measure vasomotion and interstitial oxygen tensions (PO(2)), respectively. Pretorsion control testes had a mean blood flow of 16.3 +/- 1.3 perfusion units (PU) and displayed vasomotion with a cycle frequency of 12 +/- 0.2 cycles per minute and a mean amplitude of 4.2 +/- 0.3 PU. Mean testicular interstitial PO(2) was 12.5 +/- 2.6 mm Hg, which displayed a cyclical variation of 11.9 +/- 0.4 cycles per minute with a mean amplitude of 2.8 +/- 0.8 mm Hg. During the torsion period, both mean blood flow and interstitial PO(2) decreased to approximately zero. Upon detorsion, mean microvascular blood flow and mean interstitial PO(2) values returned to values that were not significantly different from pretorsion values within 30 min; however, vasomotion and PO(2) cycling did not return, even after 24 h. It was 7 days after the repair of torsion before a regular pattern of vasomotion and PO(2) cycling returned. These results demonstrate for the first time a correlation between testicular vasomotion and interstitial PO(2) cycling, and this correlation persists after the repair of testicular torsion.     

Increased rhythmicity in hypertensive arterial smooth muscle is linked to transient receptor potential canonical channels

Vasomotion describes oscillations of arterial vascular tone due to synchronized changes of intracellular calcium concentrations. Since increased calcium influx into vascular smooth muscle cells from spontaneously hypertensive rats (SHR) has been associated with variances of transient receptor potential canonical (TRPC) channels, in the present study we tested the hypothesis that increased vasomotion in hypertension is directly linked to increased TRPC expression. Using a small vessel myograph we observed significantly increased norepinephrine‐induced vasomotion in mesenteric arterioles from SHR compared to normotensive Wistar–Kyoto (WKY) rats. Using immunoblottings we obtained significantly increased expression of TRPC1, TRPC3 and TRPC5 in mesenteric arterioles from SHR compared to WKY, whereas TRPC4 and TRPC6 showed no differences. Norepinephrine‐induced vasomotion from SHR was significantly reduced in the presence of verapamil, SKF96365, 2‐aminoethoxydiphenylborane (2‐APB) or gadolinium. Pre‐incubation of mesenteric arterioles with anti‐TRPC1 and anti‐TRPC3 antibodies significantly reduced norepinephrine‐induced vasomotion and calcium influx. Control experiments with pre‐incubation of TRPC antibodies plus their respective antigenic peptide or in the presence of anti‐β‐actin antibodies or random immunoglobulins not related to TRPC channels showed no inhibitory effects of norepinephrine‐induced vasomotion and calcium influx. Administration of candesartan or telmisartan, but not amlodipine to SHR for 16 weeks significantly reduced either the expression of TRPC1, TRPC3 and TRPC5 as well as norepinephrine‐induced vasomotion in mesenteric arterioles. In conclusion we gave experimental evidence that the increased TRPC1, TRPC3 and TRPC5 expression in mesenteric arterioles from SHR causes increased vasomotion in hypertension.     

Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia

Although vasomotion has been considered a feature of the microvascular bed under physiological conditions, it has also been observed following hypotension in several tissues. In this work, 158 mesenteric microvessels of 36 rats were investigated quantitatively in normovolemic and hemorrhaged animals, focussing on diameter changes, particularly vasomotion incidence and characteristics. The femoral arteries of Wistar rats (body weight BW = 188 +/- 23 g, mean +/- SD) anesthetized with pentobarbital were cannulated for arterial pressure (AP) monitoring and blood withdrawal. The protocol consisted of 15 min control and 30 min of hemorrhagic hypotension (AP = 52 +/- 5 mmHg, hemorrhaged vol. = 17 +/- 4 ml/kg BW). During control normovolemic conditions, analysis of mesenteric microcirculation using intravital videomicroscopy revealed neither arteriolar nor venular vasomotion. During hemorrhagic hypotension (HH) microvascular blood flow reduced to 25% of control. While venules did not show diameter changes during HH, arterioles contracted to 85 +/- 20% of control and arteriolar vasomotion appeared in 42% of the animals and 27% of the arterioles. The amplitude of arteriolar diameter change during HH relative to mean diameter and to control diameter averaged 65 +/- 24% (range: 32-129%) and 41 +/- 10% (range: 25-62%), respectively. Vasomotion analysis showed two major frequency components: 1.7 +/- 0.8 and 7.0 +/- 5.2 cycles/min. Arterioles showing vasomotion had a mean control diameter larger than the remaining arterioles and showed the largest constriction during HH. We conclude that hemorrhagic hypotension does not change venular diameter but induces arteriolar constriction and vasomotion in rat mesentery. This activity is expressed as slow waves with high amplitude and fast waves with low amplitude, and is dependent on vessel size.     

Propagation properties of vasomotion at terminal arterioles and precapillaries in the rabbit mesentery

A vasomotion activity in the mesentery of anesthetized rabbits were studied by simultaneous measurements of inside diameters at multiple sites in arterioles, precapillaries and their bifurcations. A frame-by-frame diameter determination technique was used with a microcomputer-assisted laser video disk recorder and video-image analysis system. Simultaneous intensity profiles across microvessels were continuously obtained. Applying an automatic wall surface tracer and a graphic editor to construct temporal sequences of intensity profiles, we obtained digitized data of inside diameters of microvessels, and implemented cross-correlation analysis between data sets to calculate phase differences of vasomotion at separated sites. The present analysis of the propagation of vasomotion showed that the vasomotion originated from the orifice of precapillaries at the bifurcations, spreading downstream in the precapillary. The vasomotion wave spreads both upstream and downstream along single arterioles from various origins of the vasomotion activity. The propagation velocity of vasomotion was 0.17 +/- 0.03 mm/sec (n = 19), and it became significantly slower through the branching points than along the arterioles. It is suggested that the vasomotion in terminal arterioles and precapillaries may spread through some mechanical transmission factors.     

Thermal dependence of neural activity in the hamster hippocampal slice preparation

1. Neural activity was recorded in an in vitro hamster hippocampal slice preparation while the temperature of the Ringer's solution bathing in the slice was controlled at selected levels. 2. The amplitude of the population spike (action potentials from a group of pyramidal cells) was measured as bath temperature was lowered from 35 degrees C to temperatures where a response could not be evoked. 3. Plots of population spike amplitude versus temperature have bell-shaped curves. The population spikes increased in amplitude as temperature was lowered from 35 degrees C, reached a peak amplitude between 25 and 20 degrees C, and then decreased until a response could not be evoked when temperature was further lowered. 4. These in vitro results obtained in the slice preparation are related to in vivo hippocampal studies. Results are interpreted as consistent with the proposal reviewed here that neural activity in the hippocampus plays a role at specific stages of entrance into and arousal from hibernation.     

Human initial responses to immersion in cold water at three temperatures and after hyperventilation

The present investigation was designed to examine the influence of water temperature and prior hyperventilation on some of the potentially hazardous responses evoked by immersion in cold water. Eight naked subjects performed headout immersions of 2-min duration into stirred water at 5, 10, and 15 degrees C and at 10 degrees C after 1 min of voluntary hyperventilation. Analysis of the respiratory and cardiac data collected during consecutive 10-s periods showed that, at the 0.18-m/s rate of immersion employed, differences between the variables recorded on immersion in water at 5 and 10 degrees C were due to the duration of the responses evoked rather than their magnitude during the first 20 s. The exception to this was the tidal volume of subjects, which was higher on immersion in water at 15 degrees C than at 5 or 10 degrees C. The results suggested that the respiratory drive evoked during the first seconds of immersion was more closely reflected in the rate rather than the depth of breathing at this time. Hyperventilation before immersion in water at 10 degrees C did not attenuate the respiratory responses seen on immersion. It is concluded that, during the first critical seconds of immersion, the initial responses evoked by immersion in water at 10 degrees C can represent as great a threat as those in water at 5 degrees C; also, in water at 10 degrees C, the respiratory component of this threat is not influenced by the biochemical alterations associated with prior hyperventilation.     

An infrared thermographic study of surface temperature in the euthermic woodchuck (Marmota monax).

Surface temperatures were measured in euthermic woodchucks (Marmota monax) using infrared thermography across a range of ambient temperatures from -10 degrees C to 32 degrees C. The woodchuck keeps surface temperature of the peripalpebral region uniformly high, while head and body surfaces change proportionally with ambient temperature. When ambient temperature was below 0 degrees C, all surface temperatures increased which prevents freezing. At no point did the animals appear to be unable to regulate heat exchange. This species appears to be especially well adapted to the higher temperatures it encounters in its range. Vasomotion in the feet and to a lesser extent in the pinnae was used to regulate heat loss. At ambient temperature of 32 degrees C, mean temperatures of nose surfaces were 0.2 degrees C and 0.3 degrees C less than ambient temperature suggesting a type of counter current cooling mechanism may be present.     

A model of smooth muscle cell synchronization in the arterial wall

Vasomotion is a rhythmic variation in microvascular diameter. Although known for more than 150 years, the cellular processes underlying the initiation of vasomotion are not fully understood. In the present study a model of a single cell is extended by coupling a number of cells into a tube. The simulated results point to a permissive role of cGMP in establishing intercellular synchronization. In sufficient concentration, cGMP may activate a cGMP-sensitive calcium-dependent chloride channel, causing a tight spatiotemporal coupling between release of sarcoplasmic reticulum calcium, membrane depolarization, and influx of extracellular calcium. Low [cGMP] is associated only with unsynchronized waves. At intermediate concentrations, cells display either waves or whole cell oscillations, but these remain unsynchronized between cells. Whole cell oscillations are associated with rhythmic variation in membrane potential and flow of current through gap junctions. The amplitude of these oscillations in potential grows with increasing [cGMP], and, past a certain threshold, they become strong enough to entrain all cells in the vascular wall, thereby initiating sustained vasomotion. In this state there is a rhythmic flow of calcium through voltage-sensitive calcium channels into the cytoplasm, making the frequency of established vasomotion sensitive to membrane potential. It is concluded that electrical coupling through gap junctions is likely to be responsible for the rapid synchronization across a large number of cells. Gap-junctional current between cells is due to the appearance of oscillations in the membrane potential that again depends on the entrainment of sarcoplasmic reticulum and plasma membrane within the individual cell.     

A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2

Chymases, serine proteases exclusively expressed by mast cells, have been implicated in various pathological conditions. However, the basis for these activities is not known, i.e. the in vivo substrate(s) for mast cell chymase has not been identified. In this study we show that mice lacking the chymase mouse mast cell protease 4 (mMCP-4) fail to process pro-matrix metalloprotease 9 (pro-MMP-9) to its active form in vivo, whereas both the pro and active form of MMP-9 was found in tissues of wild type mice. Moreover, the processing of pro-MMP-2 into active enzyme was markedly defective in mMCP-4 null animals. Histological analysis revealed an increase in collagen in the ear tissue of mMCP-4-deficient animals accompanied by increased ear thickness and a higher content of hydroxyproline. Furthermore, both lung and ear tissue from the knock-out animals showed a markedly increased staining for fibronectin. MMP-9 and MMP-2 are known to have a range of important activities, but the mechanisms for their activation in vivo have not been clarified previously. The present study thus indicates a key role for mast cell chymase in the regulation of pro-MMP-2 and -9 activities. Moreover, the results suggest an important role for mast cell chymase in regulating connective tissue homeostasis.     

An association between vasomotion and oxygen extraction

Vasomotion is defined as a spontaneous local oscillation in vascular tone whose function is unclear but may have a beneficial effect on tissue oxygenation. Optical reflectance spectroscopy and laser Doppler fluximetry provide unique insights into the possible mechanisms of vasomotion in the cutaneous microcirculation through the simultaneous measurement of changes in concentration of oxyhemoglobin ([HbO(2)]), deoxyhemoglobin ([Hb]), and mean blood saturation (S(mb)O(2)) along with blood volume and flux. The effect of vasomotion at frequencies <0.02 Hz attributed to endothelial activity was studied in the dorsal forearm skin of 24 healthy males. Fourier analysis identified periodic fluctuations in S(mb)O(2) in 19 out of 24 subjects, predominantly where skin temperatures were >29.3°C (X(2) = 6.19, P < 0.02). A consistent minimum threshold in S(mb)O(2) (mean: 39.4%, range: 24.0-50.6%) was seen to precede a sudden transient surge in flux, inducing a fast rise in S(mb)O(2). The integral increase in flux correlated with the integral increase in [HbO(2)] (Pearson's correlation r(2) = 0.50, P < 0.001) and with little change in blood volume suggests vasodilation upstream, responding to a low S(mb)O(2) downstream. This transient surge in flux was followed by a sustained period where blood volume and flux remained relatively constant and a steady decrease in [HbO(2)] and equal and opposite increase in [Hb] was considered to provide a measure of oxygen extraction. A measure of this oxygen extraction has been approximated by the mean half-life of the decay in S(mb)O(2) during this period. A comparison of the mean half-life in the 8 normal subjects [body mass index (BMI) <26.0 kg/m(2)] of 12.2 s and the 11 obese subjects (BMI >29.5 kg/m(2)) of 18.8 s was statistically significant (Mann Whitney, P < 0.004). The S(mb)O(2) fluctuated spontaneously in this saw tooth manner by an average of 9.0% (range 4.0-16.2%) from mean S(mb)O(2) values ranging from 30 to 52%. These observations support the hypothesis that red blood cells may act as sensors of local tissue hypoxia, through the oxygenation status of the hemoglobin, and initiate improved local perfusion to the tissue through hypoxic vasodilation.     

Physical versus pharmacological counter-measures. Studies on febrile rabbits

128 experiments were carried out on febrile rabbits at air temperatures of 8, 18, 24 and 30 degrees C in order to analyze the thermoregulatory effects and mechanisms of physical and/or pharmacological counter-measures. Fever was achieved by injection of 0.1 micrograms Salmonella typhi endotoxin (LPS)/kg into an ear vein. As the pharmacological counter-measure, injections of acetylsalicylic acid (ASA) into an ear vein were chosen. For the physical counter-measure, cooling thermodes (5 degrees C) were constructed for the abdominal skin, for the ear and for the rectum. ASA injections had no effect on the first fever maximum, even if applied 20 to 60 min before the LPS injection, but eliminated the second fever maximum. Of course, the additional hyperthermia observed at 30 degrees C ambient temperature could not be eliminated by the injections. On the other hand, cooling procedures can obviously not affect the pyrogen-induced temperature increase, but reduce the hyperthermic effect of a higher ambient temperature. Rectal cooling was more effective than ear or abdominal skin cooling. Abdominal cooling evoked an increase in metabolic heat production. Application of combined physical and pharmacological counter-measures achieved the strongest and quickest reduction of the second maximum, whereas the first maximum was not affected, as in all other experiments. The study emphasizes the necessity of taking into account the time course of the effector mechanisms in order to discriminate between hyperthermic and febrile components of temperature increase. In the initial phase cooling measures would evoke unwanted regulatory responses of the effectors, whereas during the second febrile maximum they would achieve a quicker reduction of core temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Separation of carrier mediated and vesicular release of GABA from rat brain slices.

In this study the temperature dependence of [3H]GABA release from brain slices evoked by electrical field stimulation and the Na+/K+ ATPase inhibitor ouabain was investigated. [3H]GABA has been taken up and released from hippocampal slices at rest and in response to electrical field stimulation (20 V, 10 Hz, 3 msec, 180 pulses) at 37 degrees C. When the bath temperature was cooled to 7 degrees C, during the sample collection period, the tissue uptake and the resting outflow of [3H]GABA were not significantly changed. In contrast, the stimulation-induced tritium outflow increased both in absolute amount (Bq/g) and in fractional release and the S2/S1 ratio was also higher at 7 degrees C. Perfusion of the slices with tetrodotoxin (TTX, 1 microM) inhibited stimulation-induced [3H]GABA efflux indicating that exocytotic release of vesicular origin is maintained under these conditions. 15 min perfusion with ouabain (10-20 microM) induced massive tritium release both in hippocampal and in striatal slices. However, the fraction of [3H]GABA outflow evoked by ouabain was much higher in the hippocampus than in the striatum. Sequential lowering the bath temperature from 37 degrees C to 17 degrees C completely abolished ouabain-induced [3H]GABA release in both brain regions, indicating that it is a temperature-dependent, carrier-mediated process. When the same experiments were repeated under Ca2+ free conditions, cooling the bath temperature to 17 degrees C, although substantially decreased the release but failed to completely abolish the tritium outflow evoked by ouabain, a significant part was maintained. Our results show that vesicular (field stimulation-evoked) and carrier-mediated (ouabain-induced) release of GABA is differentially affected by low temperature: while vesicular release is unaffected, carrier-mediated release is abolished at low bath temperature. Therefore, lowering the temperature offers a reliable tool to separate these two kinds of release and makes possible to study exclusively the pure neuronal release of GABA of vesicular origin.     

Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion

The hypothesis was tested that pressure and pressure pulsation modulate vascular remodeling. Arterioles ( approximately 200 microm lumen diameter) were dissected from rat cremaster muscle and studied in organoid culture. In the first series, arterioles were kept at a stable pressure level of either 50 or 100 mmHg for 3 days. Both groups showed a progressive increase in myogenic tone during the experiment. Arterioles kept at 50 mmHg showed larger endothelium-dependent dilation, compared with vessels kept at 100 mmHg on day 3. Remodeling, as indicated by the reduction in maximally dilated diameter at 100 mmHg, was larger in arterioles kept at 50 mmHg compared with 100 mmHg: 34 +/- 4.5 versus 10 +/- 4.8 microm (P < 0.05). In the second series, arterioles were subjected to a stable pressure of 60 mmHg or oscillating pressure of 60 +/- 10 mmHg (1.5 Hz) for 4 days. Pressure pulsation induced partial dilation and was associated with less remodeling: 34 +/- 4.0 versus 19 +/- 4.5 microm (P < 0.01) for stable pressure versus oscillating pressure. Vasomotion was frequently observed in all groups, and inward remodeling was larger in vessels with vasomotion: 30 +/- 2.5 microm compared with vessels that did not exhibit vasomotion: 8.0 +/- 5.0 microm (P < 0.01). In conclusion, these results indicate that remodeling is not enhanced by high pressure. Pressure pulsation causes partial dilation and reduces inward remodeling. The appearance of vasomotion is associated with enhanced inward remodeling.     

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.