Super-Resolution Ultrasound Imaging of Renal Vascular Alterations in Zucker Diabetic Fatty Rats during the Development of Diabetic Kidney Disease.

Individuals with diabetes at risk of developing diabetic kidney disease (DKD) are challenging to identify using currently available clinical methods. Prognostic accuracy and initiation of treatment could be improved by a quantification of the renal microvascular rarefaction and the increased vascular tortuosity during the development of DKD. Super-resolution ultrasound (SRUS) imaging is an in vivo technique capable of visualizing blood vessels at sizes below 75 µm. This preclinical study aimed to investigate the alterations in renal blood vessels' density and tortuosity in a type 2 diabetes rat model, Zucker diabetic fatty (ZDF) rats, as a prediction of DKD. Lean age-matched Zucker rats were used as controls. A total of 36 rats were studied, subdivided into ages of 12, 22, and 40 weeks. Measured albuminuria indicated the early stage of DKD, and the SRUS was compared with the ex vivo micro-computed tomography (µCT) of the same kidneys. Assessed using the SRUS imaging, a significantly decreased cortical vascular density was detected in the ZDF rats from 22 weeks of age compared to the healthy controls, concomitant with a significantly increased albuminuria. Already by week 12, a trend towards a decreased cortical vascular density was found prior to the increased albuminuria. The quantified vascular density in µCT corresponded with the in vivo SRUS imaging, presenting a consistently lower vascular density in the ZDF rats. Regarding vessel tortuosity, an overall trend towards an increased tortuosity was present in the ZDF rats. SRUS shows promise for becoming an additional tool for monitoring and prognosing DKD. In the future, large-scale animal studies and human trials are needed for confirmation.

Correction: A Model for Estimating Biological Age From Physiological Biomarkers of Healthy Aging: Cross-sectional Study.

[This corrects the article DOI: 10.2196/35696.].

A Model for Estimating Biological Age From Physiological Biomarkers of Healthy Aging: Cross-sectional Study.

BACKGROUND: Individual differences in the rate of aging and susceptibility to disease are not accounted for by chronological age alone. These individual differences are better explained by biological age, which may be estimated by biomarker prediction models. In the light of the aging demographics of the global population and the increase in lifestyle-related morbidities, it is interesting to invent a new biological age model to be used for health promotion. OBJECTIVE: This study aims to develop a model that estimates biological age based on physiological biomarkers of healthy aging. METHODS: Carefully selected physiological variables from a healthy study population of 100 women and men were used as biomarkers to establish an estimate of biological age. Principal component analysis was applied to the biomarkers and the first principal component was used to define the algorithm estimating biological age. RESULTS: The first principal component accounted for 31% in women and 25% in men of the total variance in the biological age model combining mean arterial pressure, glycated hemoglobin, waist circumference, forced expiratory volume in 1 second, maximal oxygen consumption, adiponectin, high-density lipoprotein, total cholesterol, and soluble urokinase-type plasminogen activator receptor. The correlation between the corrected biological age and chronological age was r=0.86 (P<.001) and r=0.81 (P<.001) for women and men, respectively, and the agreement was high and unbiased. No difference was found between mean chronological age and mean biological age, and the slope of the regression line was near 1 for both sexes. CONCLUSIONS: Estimating biological age from these 9 biomarkers of aging can be used to assess general health compared with the healthy aging trajectory. This may be useful to evaluate health interventions and as an aid to enhance awareness of individual health risks and behavior when deviating from this trajectory. TRIAL REGISTRATION: ClinicalTrials.gov NCT03680768; https://clinicaltrials.gov/ct2/show/NCT03680768. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/19209.

An abundant biliary metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides.

Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified, despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here, we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid-containing (DHA-containing) NAT C22:6 NAT was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, whereas selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high-fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT is a negative feedback mediator that limits excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.

Lack of Connexins 40 and 45 Reduces Local and Conducted Vasoconstrictor Responses in the Murine Afferent Arterioles.

The juxtaglomerular apparatus (JGA) is an essential structure in the regulation of renal function. The JGA embodies two major functions: tubuloglomerular feedback (TGF) and renin secretion. TGF is one of the mechanisms mediating renal autoregulation. It is initiated by an increase in tubular NaCl concentration at the macula densa cells. This induces a local afferent arteriolar vasoconstriction and a conducted response that can be measured several 100 µm upstream from the juxtaglomerular segment. This spread of the vasomotor response into the surrounding vasculature likely plays a key role in renal autoregulation, and it requires the presence of gap junctions, intercellular pores based on connexin (Cx) proteins. Several Cx isoforms are expressed in the JGA and in the arteriolar wall. Disruption of this communication pathway is associated with reduced TGF, dysregulation of renin secretion, and hypertension. We examine if the absence of Cx40 or Cx45, expressed in the endothelial and vascular smooth muscle cells respectively, attenuates afferent arteriolar local and conducted vasoconstriction. Afferent arterioles from wildtype and Cx-deficient mice (Cx40 and Cx45) were studied using the isolated perfused juxtamedullary nephron preparation. Vasoconstriction was induced via electrical pulse stimulation at the glomerular entrance. Inner afferent arteriolar diameter was measured locally and upstream to evaluate conducted vasoconstriction. Electrical stimulation induced local vasoconstriction in all groups. The local vasoconstriction was significantly smaller when Cx40 was absent. The vasoconstriction decreased in magnitude with increasing distance from the stimulation site. In both Cx40 and Cx45 deficient mice, the vasoconstriction conducted a shorter distance along the vessel compared to wild-type mice. In Cx40 deficient arterioles, this may be caused by a smaller local vasoconstriction. Collectively, these findings imply that Cx40 and Cx45 are central for normal vascular reactivity and, therefore, likely play a key role in TGF-induced regulation of afferent arteriolar resistance.

Influence of connexin45 on renal autoregulation.

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Lack of tone in mouse small mesenteric arteries leads to outward remodeling, which can be prevented by prolonged agonist-induced vasoconstriction.

Inward remodeling of resistance vessels is an independent risk factor for cardiovascular events. Thus far, the remodeling process remains incompletely elucidated, but the activation level of the vascular smooth muscle cell appears to play a central role. Accordingly, previous data have suggested that an antagonistic and supposedly beneficial response, outward remodeling, may follow prolonged vasodilatation. The present study aimed to determine whether 1) outward remodeling follows 3 days of vessel culture without tone, 2) a similar response can be elicited in a much shorter 4-h timeframe, and, finally, 3) whether a 4-h response can be prevented or reversed by the presence of vasoconstrictors in the medium. Cannulated mouse small mesenteric arteries were organocultured for 3 days in the absence of tone, leading to outward remodeling that continued throughout the culture period. In more acute experiments in which cannulated small mesenteric arteries were maintained in physiological saline without tone for 4 h, we detected a similar outward remodeling that proceeded at a rate several times faster. In the 4-h experimental setting, continuous vasoconstriction to ~50% tone by abluminal application of UTP or norepinephrine + neuropeptide Y prevented outward remodeling but did not cause inward remodeling. Computational modeling was used to simulate and interpret these findings and to derive time constants of the remodeling processes. It is suggested that depriving resistance arteries of activation will lead to eutrophic outward remodeling, which can be prevented by vascular smooth muscle cell activation induced by prolonged vasoconstrictor exposure. NEW & NOTEWORTHY We have established an effective 4-h method for studying outward remodeling in pressurized mouse resistance vessels ex vivo and have determined conditions that block the remodeling response. This allows for investigating the subtle but clinically highly relevant phenomenon of outward remodeling while avoiding both laborious 3-day organoid culture of cannulated vessels and in vivo experiments lasting several weeks.

Origins of variation in conducted vasomotor responses.

Regulation of blood flow in the microcirculation depends on synchronized vasomotor responses. The vascular conducted response is a synchronous dilatation or constriction, elicited by a local electrical event that spreads along the vessel wall. Despite the underlying electrical nature, however, the efficacy of conducted responses varies significantly between different initiating stimuli within the same vascular bed as well as between different vascular beds following the same stimulus. The differences have stimulated proposals of different mechanisms to account for the experimentally observed variation. Using a computational approach that allows for introduction of structural and electrophysiological heterogeneity, we systematically tested variations in both arteriolar electrophysiology and modes of stimuli. Within the same vessel, our simulations show that conduction efficacy is influenced by the type of cell being stimulated and, in case of depolarization, by the stimulation strength. Particularly, simultaneous stimulation of both endothelial and vascular smooth muscle cells augments conduction. Between vessels, the specific electrophysiology determines membrane resistance and conduction efficiency-notably depolarization or radial currents reduce electrical spread. Random cell-cell variation, ubiquitous in biological systems, only cause small or no reduction in conduction efficiency. Collectively, our simulations can explain why CVRs from hyperpolarizing stimuli tend to conduct longer than CVRs from depolarizing stimuli and why agonists like acetylcholine induce CVRs that tend to conduct longer than electrical injections. The findings demonstrate that although substantial heterogeneity is observed in conducted responses, it can be largely ascribed to the origin of electrical stimulus combined with the specific electrophysiological properties of the arteriole. We conclude by outlining a set of "principles of electrical conduction" in the microcirculation.

Less is more: minimal expression of myoendothelial gap junctions optimizes cell-cell communication in virtual arterioles.

Dysfunctional electrical signalling within the arteriolar wall is a major cause of cardiovascular disease. The endothelial cell layer constitutes the primary electrical pathway, co-ordinating contraction of the overlying smooth muscle cell (SMC) layer. As myoendothelial gap junctions (MEGJs) provide direct contact between the cell layers, proper vasomotor responses are thought to depend on a high, uniform MEGJ density. However, MEGJs are observed to be expressed heterogeneously within and among vascular beds. This discrepancy is addressed in the present study. As no direct measures of MEGJ conductance exist, we employed a computational modelling approach to vary the number, conductance and distribution of MEGJs. Our simulations demonstrate that a minimal number of randomly distributed MEGJs augment arteriolar cell-cell communication by increasing conduction efficiency and ensuring appropriate membrane potential responses in SMCs. We show that electrical coupling between SMCs must be tailored to the particular MEGJ distribution. Finally, observation of non-decaying mechanical conduction in arterioles without regeneration has been a long-standing controversy in the microvascular field. As heterogeneous MEGJ distributions provide for different conduction profiles along the cell layers, we demonstrate that a non-decaying conduction profile is possible in the SMC layer of a vessel with passive electrical properties. These intriguing findings redefine the concept of efficient electrical communication in the microcirculation, illustrating how heterogeneous properties, ubiquitous in biological systems, may have a profound impact on system behaviour and how acute local and global flow control is explained from the biophysical foundations.

Dynamic adaption of vascular morphology.

The structure of vascular networks adapts continuously to meet changes in demand of the surrounding tissue. Most of the known vascular adaptation mechanisms are based on local reactions to local stimuli such as pressure and flow, which in turn reflects influence from the surrounding tissue. Here we present a simple two-dimensional model in which, as an alternative approach, the tissue is modeled as a porous medium with intervening sharply defined flow channels. Based on simple, physiologically realistic assumptions, flow-channel structure adapts so as to reach a configuration in which all parts of the tissue are supplied. A set of model parameters uniquely determine the model dynamics, and we have identified the region of the best-performing model parameters (a global optimum). This region is surrounded in parameter space by less optimal model parameter values, and this separation is characterized by steep gradients in the related fitness landscape. Hence it appears that the optimal set of parameters tends to localize close to critical transition zones. Consequently, while the optimal solution is stable for modest parameter perturbations, larger perturbations may cause a profound and permanent shift in systems characteristics. We suggest that the system is driven toward a critical state as a consequence of the ongoing parameter optimization, mimicking an evolutionary pressure on the system.

The nanostructure of myoendothelial junctions contributes to signal rectification between endothelial and vascular smooth muscle cells.

Micro-anatomical structures in tissues have potential physiological effects. In arteries and arterioles smooth muscle cells and endothelial cells are separated by the internal elastic lamina, but the two cell layers often make contact through micro protrusions called myoendothelial junctions. Cross talk between the two cell layers is important in regulating blood pressure and flow. We have used a spatiotemporal mathematical model to investigate how the myoendothelial junctions affect the information flow between the two cell layers. The geometry of the model mimics the structure of the two cell types and the myoendothelial junction. The model is implemented as a 2D axi-symmetrical model and solved using the finite element method. We have simulated diffusion of Ca(2+) and IP(3) between the two cell types and we show that the micro-anatomical structure of the myoendothelial junction in itself may rectify a signal between the two cell layers. The rectification is caused by the asymmetrical structure of the myoendothelial junction. Because the head of the myoendothelial junction is separated from the cell it is attached to by a narrow neck region, a signal generated in the neighboring cell can easily drive a concentration change in the head of the myoendothelial protrusion. Subsequently the signal can be amplified in the head, and activate the entire cell. In contrast, a signal in the cell from which the myoendothelial junction originates will be attenuated and delayed in the neck region as it travels into the head of the myoendothelial junction and the neighboring cell.

Applicability of cable theory to vascular conducted responses.

Conduction processes in the vasculature have traditionally been described using cable theory, i.e., locally induced signals decaying passively along the arteriolar wall. The decay is typically quantified using the steady-state length-constant, λ, derived from cable theory. However, the applicability of cable theory to blood vessels depends on assumptions that are not necessarily fulfilled in small arteries and arterioles. We have employed a morphologically and electrophysiologically detailed mathematical model of a rat mesenteric arteriole to investigate if the assumptions hold and whether λ adequately describes simulated conduction profiles. We find that several important cable theory assumptions are violated when applied to small blood vessels. However, the phenomenological use of a length-constant from a single exponential function is a good measure of conduction length. Hence, λ should be interpreted as a descriptive measure and not in light of cable theory. Determination of λ using cable theory assumes steady-state conditions. In contrast, using the model it is possible to probe how conduction behaves before steady state is achieved. As ion channels have time-dependent activation and inactivation, the conduction profile changes considerably during this dynamic period with an initially longer spread of current. This may have implications in relation to explaining why different agonists have different conduction properties. Also, it illustrates the necessity of using and developing models that handle the nonlinearity of ion channels.

Estimation of the effective intercellular diffusion coefficient in cell monolayers coupled by gap junctions.

OBJECTIVE: A recently developed dye-based assay to study gap junction permeability is analysed. The assay is based on electroporation of dye into a large number of connexin 43 expressing cells, grown to confluency on electrically conductive slides. The subsequent intercellular spread of dye to non-electroporated parts of the monolayer enables estimation of the intercellular coupling. So far, the extent of dye spread has been analyzed in qualitative terms only and not in a manner based directly on the physics of the underlying diffusion process. METHODS: We apply a continuum approximation assuming that the observed dye spread can be described by Fick's law of diffusion. Deduced from Fick's law, new measures are presented which directly relate the observed spread of dye to the diffusion coefficient. RESULTS: The theoretical framework enables the estimation of an effective diffusion coefficient from Fick's law independently of the specific indicator substance used in the assay. For Lucifer Yellow, diffusion stops within few minutes after the electroporation. Therefore only an order-of-magnitude estimate of the diffusion coefficient can be given for this dye. CONCLUSION: In terms of the underlying diffusion coefficient, the hitherto used measures give a relatively poor degree of quantification. In contrast, the present methods may yield direct information on the effective intercellular diffusion coefficient and hence provide additional and more precise information as to the permeability modulating effect of various substances.

BKCa and KV channels limit conducted vasomotor responses in rat mesenteric terminal arterioles.

Intracellular Ca(2+) signals underlying conducted vasoconstriction to local application of a brief depolarizing KCl stimulus was investigated in rat mesenteric terminal arterioles (<40 µm). Using a computer model of an arteriole segment comprised of coupled endothelial cells (EC) and vascular smooth muscle cells (VSMC) simulations of both membrane potential and intracellular [Ca(2+)] were performed. The "characteristic" length constant, λ, was approximated using a modified cable equation in both experiments and simulations. We hypothesized that K(+) conductance in the arteriolar wall limit the electrotonic spread of a local depolarization along arterioles by current dissipation across the VSMC plasma membrane. Thus, we anticipated an increased λ by inhibition of voltage-activated K(+) channels. Application of the BK(Ca) channel blocker iberiotoxin (100 nM) onto mesenteric arterioles in vitro and inhibition of BK(Ca) channel current in silico increased λ by 34% and 32%, respectively. Similarly, inhibition of K(V) channels in vitro (4-aminopyridine, 1 mM) or in silico increased λ by 41% and 21%, respectively. Immunofluorescence microscopy demonstrated expression of BK(Ca), Kv1.5, Kv2.1, but not Kv1.2, in VSMCs of rat mesenteric terminal arterioles. Our results demonstrate that inhibition of voltage-activated K(+) channels enhance vascular-conducted responses to local depolarization in terminal arterioles by increasing the membrane resistance of VSMCs. These data contribute to our understanding of how differential expression patterns of voltage-activated K(+) channels may influence conducted vasoconstriction in small arteriolar networks. This finding is potentially relevant to understanding the compromised microcirculatory blood flow in systemic vascular diseases such as diabetes mellitus and hypertension.

Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries.

AIMS: We have previously characterized a cGMP-dependent Ca(2+)-activated Cl(-) current in vascular smooth muscle cells (SMCs) and have shown its dependence on bestrophin-3 expression. We hypothesize that this current is important for synchronization of SMCs in the vascular wall. In the present study, we aimed to test this hypothesis by transfecting rat mesenteric small arteries in vivo with siRNA specifically targeting bestrophin-3. METHODS AND RESULTS: The arteries were tested 3 days after transfection in vitro for isometric force development and for intracellular Ca(2+) in SMCs. Bestrophin-3 expression was significantly reduced compared with arteries transfected with mutated siRNA. mRNA levels for bestrophin-1 and -2 were also significantly reduced by bestrophin-3 down-regulation. This is suggested to be secondary to specific bestrophin-3 down-regulation since siRNAs targeting different exons of the bestrophin-3 gene had identical effects on bestrophin-1 and -2 expression. The transfection affected neither the maximal contractile response nor the sensitivity to norepinephrine and arginine-vasopressin. The amplitude of agonist-induced vasomotion was significantly reduced in arteries down-regulated for bestrophins compared with controls, and asynchronous Ca(2+) waves appeared in the SMCs. The average frequency of vasomotion was not different. 8Br-cGMP restored vasomotion in arteries where the endothelium was removed, but oscillation amplitude was still significantly less in bestrophin-down-regulated arteries. Thus, vasomotion properties were consistent with those previously characterized for rat mesenteric small arteries. Data from our mathematical model are consistent with the experimental results. CONCLUSION: This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.

Significance of microvascular remodelling for the vascular flow reserve in hypertension.

Vascular flow reserve (VFR) is the relative increase in tissue perfusion from the resting state to a state with maximum vasodilatation. Longstanding hypertension reduces the VFR, which in turn reduces the maximum working capacity of the tissue. In principle, both inward arteriolar remodelling and rarefaction of the microvascular network may contribute to this reduction. These processes are known to occur simultaneously in the microcirculation of the hypertensive individual and both cause a reduction in the luminal trans-sectional area available for perfusion. Which of them is the main factor responsible for the reduction in VFR is, however, not known. Here we present simulations performed on large microvascular networks to assess the VFR in various situations. Particular attention is paid to the VFR in networks in which the vessels have structurally adapted to a sustained increase in pressure by inward eutrophic remodelling (IER), i.e. by redistributing the same amount of wall material around a smaller lumen. Collectively, the results indicate that the IER may not per se be the main factor responsible for the hypertensive reduction in VFR. Rather, it may be explained by the presence of arteriolar and capillary rarefaction.

A tissue in the tissue: models of microvascular plasticity.

The microcirculation is a dense space-filling network that, with few exceptions, invests every tissue in the body. To maintain an optimal function, any lasting change in volume or physiological activity level of a tissue is met with a corresponding structural change in the supplying microvascular network. The pronounced plasticity and the inherently complex nature of vascular networks have spurred an enduring interest in mathematical modeling of the microcirculation. This has been advanced by the continuous increase in computing power over recent decades enabling simulation of increasingly detailed models of microvascular rarefaction, remodeling and growth. In the present paper we review some of the models of microvascular adaptation that have appeared in the literature within the last two decades. We focus on models in which local vessel structure and/or network structure is allowed to change, either in an adaptive manner or as consequence of directly imposed alterations. Most of the early models are concerned primarily with vessel diameter and flow simulations and do not, in many cases, explicitly take into consideration the vascular wall. More recent models typically include the structural and mechanical properties of the vascular wall itself. This has allowed the emerging concept of tone as a pervasive factor in remodeling to enter microvascular models and this concept may become a cornerstone in future modeling work. The main goal in the present paper is briefly to review and discuss some of the mechanisms in the different models which govern microvascular adaptation and to point to some possible future directions for models of microvessels and microvascular networks.

Heterogeneity and weak coupling may explain the synchronization characteristics of cells in the arterial wall.

Vascular smooth muscle cells (SMCs) exhibit different types of calcium dynamics. Static vascular tone is associated with unsynchronized calcium waves and the developed force depends on the number of recruited cells. Global calcium transients synchronized among a large number of cells cause rhythmic development of force known as vasomotion. We present experimental data showing a considerable heterogeneity in cellular calcium dynamics in the vascular wall. In stimulated vessels, some SMCs remain quiescent, whereas others display waves of variable frequency. At the onset of vasomotion, all SMCs are enrolled into synchronized oscillation. Simulations of coupled SMCs show that the experimentally observed cellular recruitment, the presence of quiescent cells and the variation in oscillation frequency may arise if the cell population is phenotypically heterogeneous. In this case, quiescent cells can be entrained at the onset of vasomotion by the collective driving force from the synchronized oscillations in the membrane potential of the surrounding cells. Partial synchronization arises with an increase in the concentration of cyclic guanosine monophosphate, but in a heterogeneous cell population complete synchronization also requires a high-conductance pathway that provides strong coupling between the cells.

A mechanism for arteriolar remodeling based on maintenance of smooth muscle cell activation.

Structural adaptation in arterioles is part of normal vascular physiology but is also seen in disease states such as hypertension. Smooth muscle cell (SMC) activation has been shown to be central to microvascular remodeling. We hypothesize that, in a remodeling process driven by SMC activation, stress sensitivity of the vascular wall is a key element in the process of achieving a stable vascular structure. We address whether the adaptive changes in arterioles under different conditions can arise through a common mechanism: remodeling in a stress-sensitive wall driven by a shift in SMC activation. We present a simple dynamic model and show that structural remodeling of the vessel radius by rearrangement of the wall material around a lumen of a different diameter and driven by differences in SMC activation can lead to vascular structures similar to those observed experimentally under various conditions. The change in structure simultaneously leads to uniform levels of circumferential wall stress and wall strain, despite differences in transmural pressure. A simulated vasoconstriction caused by increased SMC activation leads to inward remodeling, whereas outward remodeling follows relaxation of the vascular wall. The results are independent of the specific myogenic properties of the vessel. The simulated results are robust in the face of parameter changes and, hence, may be generalized to vessels from different vascular beds.

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.