Autoregulation and conduction of vasomotor responses in a mathematical model of the rat afferent arteriole

We have formulated a mathematical model for the rat afferent arteriole (AA). Our model consists of a series of arteriolar smooth muscle cells and endothelial cells, each of which represents ion transport, cell membrane potential, and gap junction coupling. Cellular contraction and wall mechanics are also represented for the smooth muscle cells. Blood flow through the AA lumen is described by Poiseuille flow. The AA model's representation of the myogenic response is based on the hypothesis that changes in hydrostatic pressure induce changes in the activity of nonselective cation channels. The resulting changes in membrane potential then affect calcium influx through changes in the activity of the voltage-gated calcium channels, so that vessel diameter decreases with increasing pressure values. With this configuration, the model AA maintains roughly stable renal blood flow within a physiologic range of blood flow pressure. Model simulation of vasoconstriction initiated from local stimulation also agrees well with findings in the experimental literature, notably those of Steinhausen et al. (Steinhausen M, Endlich K, Nobiling R, Rarekh N, Schütt F. J Physiol 505: 493-501, 1997), which indicated that conduction of vasoconstrictive response decays more rapidly in the upstream flow direction than downstream. The model can be incorporated into models of integrated renal hemodynamic regulation.     

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.     

Control and Modulation of Fluid Flow in the Rat Kidney

We have developed a mathematical model of the rat’s renal hemodynamics in the nephron level, and used that model to study flow control and signal transduction in the rat kidney. The model represents an afferent arteriole, glomerular filtration, and a segment of a short-loop nephron. The model afferent arteriole is myogenically active and represents smooth muscle membrane potential and electrical coupling. The myogenic mechanism is based on the assumption that the activity of nonselective cation channels is shifted by changes in transmural pressure, such that elevation in pressure induces vasoconstriction, which increases resistance to blood flow. From the afferent arteriole’s fluid delivery output, glomerular filtration rate is computed, based on conservation of plasma and plasma protein. Chloride concentration is then computed along the renal tubule based on solute conservation that represents water reabsorption along the proximal tubule and the water-permeable segment of the descending limb, and chloride fluxes driven by passive diffusion and active transport. The model’s autoregulatory response is predicted to maintain stable renal blood flow within a physiologic range of blood pressure values. Power spectra associated with time series predicted by the model reveal a prominent fundamental peak at ～165 mHz arising from the afferent arteriole’s spontaneous vasomotion. Periodic external forcings interact with vasomotion to introduce heterodynes into the power spectra, significantly increasing their complexity.     

Systolic and mean blood pressures and afferent arteriolar myogenic response dynamics: a modeling approach

The afferent arteriolar myogenic response contributes to the autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and plays an essential role in protecting the kidney against hypertensive injury. Systolic blood pressure (SBP) is most closely linked to renal injury, and a myogenic response coupled to this signal would facilitate renal protection, whereas mean blood pressure (MBP) influences RBF and GFR. The relative role of SBP vs. MBP as the primary determinant of myogenic tone is an area of current controversy. Here, we describe two mathematical models, Model-Avg and Model-Sys, that replicate the different delays and time constants of vasoconstrictor and vasodilator phases of the myogenic responses of the afferent arteriole. When oscillating pressures are applied, the MBP determines the magnitude of the myogenic response of Model-Avg, and the SBP determines the response of Model-Sys. Simulations evaluating the responses of both models to square-wave pressure oscillations and to narrow pressure pulses show decidedly better agreement between Model-Sys and afferent arteriolar responses observed in cortical nephrons in the in vitro hydronephrotic kidney model. Analysis showing that the difference in delay times of the vasoconstrictor and vasodilator phases determines the frequency range over which SBP triggers Model-Sys's response was confirmed with simulations using authentic blood pressure waveforms. These observations support the postulate that SBP is the primary determinant of the afferent arteriole's myogenic response and indicate that differences in the delays in initiation vs. termination of the response, rather than in time constants, are integral to this phenomenon.     

Mechanical control of cation channels in the myogenic response

Microcirculatory vessel response to changes in pressure, known as the myogenic response, is a key component of a tissue's ability to regulate blood flow. Experimental studies have not clearly elucidated the mechanical signal in the vessel wall governing steady-state reduction in vessel diameter upon an increase in intraluminal pressure. In this study, a multiscale computational model is constructed from established models of vessel wall mechanics, vascular smooth muscle (VSM) force generation, and VSM Ca(2+) handling and electrophysiology to compare the plausibility of vessel wall stress or strain as an effective mechanical signal controlling steady-state vascular contraction in the myogenic response. It is shown that, at the scale of a resistance vessel, wall stress, and not stretch (strain), is the likely physiological signal controlling the steady-state myogenic response. The model is then used to test nine candidate VSM stress-controlled channel variants by fitting two separate sets of steady-state myogenic response data. The channel variants include nonselective cation (NSC), supplementary Ca(2+) and Na(+), L-type Ca(2+), and large conductance Ca(2+)-activated K(+) channels. The nine variants are tested in turn, and model fits suggest that stress control of Ca(2+) or Na(+) influx through NSC, supplementary Ca(2+) or Na(+), or L-type Ca(2+) channels is sufficient to produce observed steady-state diameter changes with pressure. However, simulations of steady-state VSM membrane potential, cytosolic Ca(2+), and Na(+) with pressure show only that Na(+) influx through NSC channel also generates known trends with increasing pressure, indicating that stress-controlled Na(+) influx through NSC is sufficient to generate the myogenic response.     

Rho kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity

The hypothesis that Rho kinase is involved in myogenic reactivity was investigated in pressurized rat tail small arteries using videomicroscopic diameter determination and calcium fluorimetry. The potent Rho kinase inhibitor Y-27632 reversibly increased vessel diameter at 80 mmHg without changing the intracellular calcium concentration ([Ca](i)) shifting the relationship between diameter change and [Ca](i) to higher calcium levels. Neither endothelium removal nor inhibition of neural transmission affected the Y-27632-induced effect. Y-27632 at 3 x 10(-6) mol/l attenuated the myogenic response in the pressure range from 10 to 120 mmHg, shifting the relationship between vessel tone and [Ca](i) to higher calcium levels. In addition, the Y-27632-induced shift of the relationship between vessel tone and [Ca](i) was larger at 80 than at 10 mmHg. These results suggest that smooth muscle cell Rho kinase in rat tail small arteries 1) is in an active state partly determining the level of the myogenic tone, and 2) alters the strength of the myogenic response by changing calcium sensitivity, probably caused by the pressure-induced activation of the kinase.     

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.     

Impaired myogenic constriction of the renal afferent arteriole in a mouse model of reduced βENaC expression

Previous studies demonstrate a role for β epithelial Na(+) channel (βENaC) protein as a mediator of myogenic constriction in renal interlobar arteries. However, the importance of βENaC as a mediator of myogenic constriction in renal afferent arterioles, the primary site of development of renal vascular resistance, has not been determined. We colocalized βENaC with smooth muscle α-actin in vascular smooth muscle cells in renal arterioles using immunofluorescence. To determine the importance of βENaC in myogenic constriction in renal afferent arterioles, we used a mouse model of reduced βENaC (βENaC m/m) and examined pressure-induced constrictor responses in the isolated afferent arteriole-attached glomerulus preparation. We found that, in response to a step increase in perfusion pressure from 60 to 120 mmHg, the myogenic tone increased from 4.5 ± 3.7 to 27.3 ± 5.2% in +/+ mice. In contrast, myogenic tone failed to increase with the pressure step in m/m mice (3.9 ± 0.8 to 6.9 ± 1.4%). To determine the importance of βENaC in myogenic renal blood flow (RBF) regulation, we examined the rate of change in renal vascular resistance following a step increase in perfusion pressure in volume-expanded animals. We found that, following a step increase in pressure, the rate of myogenic correction of RBF is inhibited by 75% in βENaC m/m mice. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of βENaC.     

Zinc-Finger Nuclease Knockout of Dual-Specificity Protein Phosphatase-5 Enhances the Myogenic Response and Autoregulation of Cerebral Blood Flow in FHH.1BN Rats

We recently reported that the myogenic responses of the renal afferent arteriole (Af-Art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow (RBF and CBF) were impaired in Fawn Hooded hypertensive (FHH) rats and were restored in a FHH.1^BN congenic strain in which a small segment of chromosome 1 from the Brown Norway (BN) containing 15 genes including dual-specificity protein phosphatase-5 (Dusp5) were transferred into the FHH genetic background. We identified 4 single nucleotide polymorphisms in the Dusp5 gene in FHH as compared with BN rats, two of which altered CpG sites and another that caused a G155R mutation. To determine whether Dusp5 contributes to the impaired myogenic response in FHH rats, we created a Dusp5 knockout (KO) rat in the FHH.1^BN genetic background using a zinc-finger nuclease that introduced an 11 bp frame-shift deletion and a premature stop codon at AA121. The expression of Dusp5 was decreased and the levels of its substrates, phosphorylated ERK1/2 (p-ERK1/2), were enhanced in the KO rats. The diameter of the MCA decreased to a greater extent in Dusp5 KO rats than in FHH.1^BN and FHH rats when the perfusion pressure was increased from 40 to 140 mmHg. CBF increased markedly in FHH rats when MAP was increased from 100 to 160 mmHg, and CBF was better autoregulated in the Dusp5 KO and FHH.1^BN rats. The expression of Dusp5 was higher at the mRNA level but not at the protein level and the levels of p-ERK1/2 and p-PKC were lower in cerebral microvessels and brain tissue isolated from FHH than in FHH.1^BN rats. These results indicate that Dusp5 modulates myogenic reactivity in the cerebral circulation and support the view that a mutation in Dusp5 may enhance Dusp5 activity and contribute to the impaired myogenic response in FHH rats.     

Myogenic reactivity and resistance distribution in the coronary arterial tree: a model study

The objectives of this study were to evaluate the myogenic behavior of blood vessels and their interaction within the coronary arterial tree and to evaluate the possible role of the myogenic response in autoregulation. The model consists of 10 compartments in series, each representing a class of vessel sizes. Diameter and resistance in each class are determined by their value at full dilation (d(p,) R(p)) and by the myogenic response. Three distributions of R(p) and three distributions of myogenic strength, M(i) (slope of pressure-diameter curve, range -0.05 to -0.4%/mmHg) were evaluated (9 cases). It was found that larger vessels attenuate the myogenic activity of smaller vessels and that myogenic responsiveness is sufficient to achieve autoregulation. When M(i) has a maximum in vessels of 84 microm, the maximum effect of perfusion pressure on active diameter occurs in vessels between 123 and 181 microm, depending on the distribution of R(p). Distribution of resistance and control mechanisms in the coronary arterial tree are important for interpretation of individual vessel responses as observed in vivo.     

Tyrosine phosphorylation modulates arteriolar tone but is not fundamental to myogenic response

The present study investigated the role of protein tyrosine phosphorylation in myogenic responsiveness of rat skeletal muscle arterioles. Arteriolar segments were cannulated and pressurized without intraluminal flow. All vessels studied developed spontaneous tone and demonstrated significant myogenic constriction to step changes in pressure with a resultant increase in myogenic tone over an intraluminal pressure range of 50-150 mmHg. Step increases in intraluminal pressure from 50 to 120 mmHg caused a rapid and sustained elevation in intracellular [Ca(2+)], as measured using fura 2. Vessels with myogenic tone dilated in response to tyrosine kinase inhibitors genistein (10 or 30 microM) and tyrphostin A47 (10 or 30 microM) and constricted to the tyrosine phosphatase inhibitor pervanadate (1 or 10 microM). Despite the dilator effect, myogenic reactivity was not blocked by the inhibitors. Daidzein (10 microM), a compound structurally similar to genistein but without tyrosine kinase-inhibiting activity, did not alter vessel tone or myogenic responses. Preincubation of arterioles with genistein or tyrphostin A47 did not significantly alter baseline arteriolar [Ca(2+)], and neither drug reduced the increase in [Ca(2+)] following an acute increase in intraluminal pressure. Constriction induced by pervanadate (10 microM) was not accompanied by a significant increase in intracellular [Ca(2+)], even though removal of extracellular Ca(2+) reversed the constriction. Examination of smooth muscle tyrosine phosphorylation, using a fluorescent phosphotyrosine antibody and confocal microscopy, showed that increased intraluminal pressure resulted in an increase in anti-phosphotyrosine fluorescence. Because manipulation of tyrosine kinase activity was found to alter vessel diameter, these data support a role for tyrosine phosphorylation in modulation of arteriolar tone. However, the results indicate that acute arteriolar myogenic constriction does not require tyrosine phosphorylation.     

Effect of nitrendipine on cardiac and renal lesions and arterial hypertrophy

A low dose of nitrendipine (1 mg/kg twice daily) ameliorated the percent incidence and severity of vascular lesions in the kidney and heart induced by deoxycorticosterone (DOC). Less protection was offered by administration of 1 mg/kg of the calcium antagonist once daily. A lower dose of the antagonist (0.5 mg/kg) administered twice daily produced almost no protection against myocardial scars, but the percent incidence and severity of renal tubular casts and glomerular changes were similar to those following injection of 1 mg/kg of the antagonist twice daily. DOC induced hypertrophy of the media in aorta, coronary artery and renal interlobular artery and renal arteriole. Neither 1 mg/kg once or twice daily nor 0.5 mg twice daily of calcium antagonist modified the hypertrophy of the arterial vasculature in the hypertensive DOC group. We conclude that a low dose of the calcium antagonist dissociates at least in part lesions but not hypertrophy from the increased systolic blood pressure, because the antagonist protects against vascular lesions induced by the hypertension. The antagonist likely acts on the endothelial cell of the vessels alone or combined with an effect on the vascular smooth muscle cells.     

A new method for assessing arteriolar diameter and hemodynamic resistance using image analysis of vessel lumen

To characterize the nonuniform diameter response in a blood vessel after a given stimulus (e.g., arteriolar conducted response), frequent serial diameter measurements along the vessel length are required. We used an advanced image analysis algorithm (the "discrete dynamic contour") to develop a quick, reliable method for serial luminal diameter measurements along the arteriole visualized by intravital video microscopy. With the use of digitized images of the arteriole and computer graphics, the method required an operator to mark the image of the two inner edges of the arteriole at several places along the arteriolar length. The algorithm then "filled in" these marks to generate two continuous contours that "hugged" these edges. A computer routine used these contours to determine luminal diameters every 20 microm. Based on these diameters and on Poiseuille's law, the routine also estimated the hemodynamic resistance of the blood vessel. To demonstrate the usefulness of the method, we examined the character of spatial decay of KCl-induced conducted constriction along approximately 500-microm-long arteriolar segments and the KCl-induced increase in hemodynamic resistance computed for these segments. The decay was only modestly fitted by a simple exponential, and the computed increase in resistance (i.e., 5- to 70-fold) was only modestly predicted by resistance increase based on our mathematical model involving measurements at two arteriolar sites (Tyml K, Wang X, Lidington D, and Oullette Y. Am J Physiol Heart Circ Physiol 281: H1397-H1406, 2001). We conclude that our method provides quick, reliable serial diameter measurements. Because the change in hemodynamic resistance could serve as a sensitive index of conducted response, use of this index in studies of conducted response may lead to new mechanistic insights on the response.     

Effects of aging on vasoconstrictor and mechanical properties of rat skeletal muscle arterioles

Exercise capacity and skeletal muscle blood flow during exercise are reduced with advancing age. This reduction in blood flow capacity may be related to increased reactivity of skeletal muscle resistance vessels to vasoconstrictor stimuli. The purpose of this study was to test the hypothesis that aging results in increased vasoconstrictor responses of skeletal muscle resistance arterioles. First-order (1A) arterioles (90-220 microm) from the gastrocnemius and soleus muscles of young (4 mo) and aged (24 mo) Fischer-344 rats were isolated, cannulated, and pressurized via hydrostatic reservoirs. Vasoconstriction in response to increases in norepinephrine (NE; 1 x 10(-9)-1 x 10(-4) M) and KCl (20-100 mM) concentrations and increases in intraluminal pressure (10-130 cmH(2)O) were evaluated in the absence of flow. Responses to NE and KCl were similar in both soleus and gastrocnemius muscle arterioles from young and aged rats. In contrast, active myogenic responses to changes in intraluminal pressure were diminished in soleus and gastrocnemius arterioles from aged rats. To assess whether alterations in the mechanical properties of resistance arterioles underlie altered myogenic responsiveness, passive diameter responses to pressure and mechanical stiffness were evaluated. There was no effect of age on the structural behavior (passive pressure-diameter relationship) or stiffness of arterioles from either the soleus or gastrocnemius muscles. These results suggest that aging does not result in a nonspecific decrease in vasoconstrictor responsiveness of skeletal muscle arterioles. Rather, aging-induced adaptations of vasoreactivity of resistance arterioles appear to be limited to mechanisms that are uniquely involved in the signaling of the myogenic response.     

Transient increases in diameter and [Ca(2+)](i) are not obligatory for myogenic constriction

Studies were performed to determine the significance of temporal variation in vascular smooth muscle Ca(2+) signaling during acute arteriolar myogenic constriction and, in particular, the importance of the stretch-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) transient in attaining a steady-state mechanical response. Rat cremaster arterioles (diameter approximately 100 microm) were dissected from surrounding tissues, and vessel segments were pressurized in the absence of intraluminal flow. For [Ca(2+)](i) measurements, vessels were loaded with fura 2 and fluorescence emitted by excitation at 340 and 380 nm was measured using video-based image analysis. Ca(2+) and diameter responses were examined after increases in intravascular pressure were applied as an acute step increase or a ramp function. Additional studies examined the effect of longitudinal vessel stretch on [Ca(2+)](i) and arteriolar diameter. Step increase in intraluminal pressure (from 50 to 120 mmHg) caused biphasic change in [Ca(2+)](i) and diameter. [Ca(2+)](i) transiently increased to 114.0 +/- 2.0% of basal levels and subsequently declined to 106.7 +/- 4.4% at steady state. Diameter initially distended to 125.4 +/- 2.1% of basal levels before constricting to 71.1 +/- 1.2%. In contrast, when the same pressure increase was applied as a ramp function (over 5 min) transient vessel distension and transient increase in [Ca(2+)](i) were prevented, yet at steady state vessels constricted to 71.3 +/- 2.5%. Longitudinal stretch resulted in a large [Ca(2+)](i) transient (158 +/- 19% of basal) that returned to baseline despite maintenance of the stretch stimulus. The data demonstrate that the initial vessel distension (reflecting myocyte stretch) and associated global [Ca(2+)](i) transient are not obligatory for myogenic contraction. Thus, although arteriolar smooth muscle cells are responsive to acute stretch, the resulting changes in myogenic tone may be more closely related to other mechanical variables such as wall tension.     

Vascular smooth muscle cell stress as a determinant of cerebral artery myogenic tone

Although the level of myogenic tone (MT) varies considerably from vessel to vessel, the regulatory mechanisms through which the actual diameter set point is determined are not known. We hypothesized that a unifying principle may be the equalization of active force at the contractile filament level, which would be reflected in a normalization of wall stress or, more specifically, media stress. Branched segments of rat cerebral arteries ranging from <50 microm to >200 microm in diameter were cannulated and held at 60 mmHg with the objectives of: 1) evaluating the relationship between arterial diameter and the extent of myogenic tone, 2) determining whether differences in MT correlate with changes in cytosolic calcium ([Ca(2+)](i)), and 3) testing the hypothesis that a normalization of wall or media stress occurs during the process of tone development. The level of MT increased significantly as vessel size decreased. At 60 mmHg, vascular smooth muscle [Ca(2+)](i) concentrations were similar in all vessels studied (averaging 230 +/- 9.2 nM) and not correlated with vessel size or the extent of tone. Wall tension increased with increasing arterial size, but wall stress and media stress were similar in large versus small arteries. Media stress, in particular, was quite uniform in all vessels studied. Both morphological and calcium data support the concept of equalization of media stress (and, hence, vascular smooth muscle cell stress and force) as an underlying mechanism in determining the level of tone present in any particular vessel. The equalization of active (vascular smooth muscle cell) stress may thus explain differences in MT observed in the different-sized vessels constituting the arterial network and provide a link between arterial structure and function, in both short- and long-term (hypertension) pressure adaptation.     

Effect of nitrendipine on cardiac and renal lesions and arterial hypertrophy. Protective effect of a low dose of calcium antagonist in deoxycorticosterone-induced hypertensive rats

A low dose of nitrendipine (1 mg/kg twice daily) ameliorated the percent incidence and severity of vascular lesions in the kidney and heart induced by deoxycorticosterone (DOC). Less protection was offered by administration of 1 mg/kg of the calcium antagonist once daily. A lower dose of the antagonist (0.5 mg/kg) administered twice daily produced almost no protection against myocardial scars, but the percent incidence and severity of renal tubular casts and glomerular changes were similar to those following injection of 1 mg/kg of the antagonist twice daily. DOC induced hypertrophy of the media in aorta, coronary artery and renal interlobular artery and renal arteriole. Neither 1 mg/kg once or twice daily nor 0.5 mg twice daily of calcium antagonist modified the hypertrophy of the arterial vasculature in the hypertensive DOC group. We conclude that a low dose of the calcium antagonist dissociates at least in part lesions but not hypertrophy from the increased systolic blood pressure, because the antagonist protects against vascular lesions induced by the hypertension. The antagonist likely acts on the endothelial cell of the vessels alone or combined with an effect on the vascular smooth muscle cells.     

Venular endothelium-derived NO can affect paired arteriole: a computational model

Venular endothelial cells can release nitric oxide (NO) in response to intraluminal flow both in isolated venules and in vivo. Experimental studies suggest that venular endothelium-released NO causes dilation of the adjacent paired arteriole. In the vascular wall, NO stimulates its target hemoprotein, soluble guanylate cyclase (sGC), which relaxes smooth muscle cells. In this study, a computational model of NO transport for an arteriole and venule pair was developed to determine the importance of the venular endothelium-released NO and its transport to the adjacent arteriole in the tissue. The model predicts that the tissue NO levels are affected within a wide range of parameters, including NO-red blood cell reaction rate and NO production rate in the arteriole and venule. The results predict that changes in the venular NO production affected not only venular endothelial and smooth muscle NO concentration but also endothelial and smooth muscle NO concentration in the adjacent arteriole. This suggests that the anatomy of microvascular tissue can permit the transport of NO from arteriolar to venular side, and vice versa, and may provide a mechanism for dilation of proximal arterioles by venules. These results will have significant implications for our understanding of tissue NO levels in both physiological and pathophysiological conditions.     

Integrins and mechanotransduction of the vascular myogenic response

This review summarizes what is currently known about the role of integrins in the vascular myogenic response. The myogenic response is the rapid and maintained constriction of a blood vessel in response to pressure elevation. A role for integrins in this process has been suggested because these molecules form an important mechanical link between the extracellular matrix and the vascular smooth muscle cytoskeleton. We briefly summarize evidence for a general role of integrins in mechanotransduction. We then describe the integrin subunit combinations known to exist in smooth muscle and the vascular wall matrix proteins that may interact with these integrins. We then discuss the effects of integrin-specific peptides and antibodies on vascular tone and on calcium entry mechanisms in vascular smooth muscle. Because integrin function is linked to the cytoskeleton, we discuss evidence for the role of the cytoskeleton in determining myogenic responsiveness. Finally, we analyze evidence that integrin-linked signaling pathways, such as those involving protein tyrosine phosphorylation cascades and mitogen-activated protein kinases, are required for myogenic tone.     

Theoretical model of blood flow autoregulation: roles of myogenic, shear-dependent, and metabolic responses

The autoregulation of blood flow, the maintenance of almost constant blood flow in the face of variations in arterial pressure, is characteristic of many tissue types. Here, contributions to the autoregulation of pressure-dependent, shear stress-dependent, and metabolic vasoactive responses are analyzed using a theoretical model. Seven segments, connected in series, represent classes of vessels: arteries, large arterioles, small arterioles, capillaries, small venules, large venules, and veins. The large and small arterioles respond actively to local changes in pressure and wall shear stress and to the downstream metabolic state communicated via conducted responses. All other segments are considered fixed resistances. The myogenic, shear-dependent, and metabolic responses of the arteriolar segments are represented by a theoretical model based on experimental data from isolated vessels. To assess autoregulation, the predicted flow at an arterial pressure of 130 mmHg is compared with that at 80 mmHg. If the degree of vascular smooth muscle activation is held constant at 0.5, there is a fivefold increase in blood flow. When myogenic variation of tone is included, flow increases by a factor of 1.66 over the same pressure range, indicating weak autoregulation. The inclusion of both myogenic and shear-dependent responses results in an increase in flow by a factor of 2.43. A further addition of the metabolic response produces strong autoregulation with flow increasing by a factor of 1.18 and gives results consistent with experimental observation. The model results indicate that the combined effects of myogenic and metabolic regulation overcome the vasodilatory effect of the shear response and lead to the autoregulation of blood flow.