Cellular communication among smooth muscle cells: The role of membrane potential via connexins.

Communication via action potentials among neurons has been extensively studied. However, effective communication without action potentials is ubiquitous in biological systems, yet it has received much less attention in comparison. Multi-cellular communication among smooth muscles is crucial for regulating blood flow, for example. Understanding the mechanism of this non-action potential communication is critical in many cases, like synchronization of cellular activity, under normal and pathological conditions. In this paper, we employ a multi-scale asymptotic method to derive a macroscopic homogenized bidomain model from the microscopic electro-neutral (EN) model. This is achieved by considering different diffusion coefficients and incorporating nonlinear interface conditions. Subsequently, the homogenized macroscopic model is used to investigate communication in multi-cellular tissues. Our computational simulations reveal that the membrane potential of syncytia, formed by interconnected cells via connexins, plays a crucial role in propagating oscillations from one region to another, providing an effective means for fast cellular communication. Statement of Significance: In this study, we investigated cellular communication and ion transport in vascular smooth muscle cells, shedding light on their mechanisms under normal and abnormal conditions. Our research highlights the potential of mathematical models in understanding complex biological systems. We developed effective macroscale electro-neutral bi-domain ion transport models and examined their behavior in response to different stimuli. Our findings revealed the crucial role of connexinmediated membrane potential changes and demonstrated the effectiveness of cellular communication through syncytium membranes. Despite some limitations, our study provides valuable insights into these processes and emphasizes the importance of mathematical modeling in unraveling the complexities of cellular communication and ion transport.

Multifold Post-Modification of Macrocycles and Cages by Isocyanate-Induced Azadefluorination Cyclisation.

We present the multiple post-modification of organic macrocycles and cages, introducing functional groups into two- and three-dimensional supramolecular scaffolds bearing fluorine substituents, which opens up new possibilities in multi-step supramolecular chemistry employing the vast chemical space of readily available isocyanates. The mechanism and scope of the reaction that proceeds after isocyanate addition to the benzylamine motif via an azadefluorination cyclisation (ADFC) were investigated using DFT calculations, and a series of aromatic isocyanates with different electronic properties were tested. The compounds show excellent chemical stability and were fully characterised. They can be used for subsequent cross-coupling reactions, and ADFC can be used directly to generate cross-linked membranes from macrocycles or cages when using ditopic isocyanates. Single-crystal X-ray (SC-XRD) analysis shows the proof of the formation of the desired supramolecular entity together with the connectivity predicted by calculations and from 19F NMR shifts, allowing the late-stage functionalisation of self-assembled macrocycles and cages by ADFC.

The Reversal Characteristics of GABAergic Neurons: A Neurovascular Model.

Neurovascular coupling (NVC) is the ability to locally adjust vascular resistance as a function of neuronal activity. Recent experiments have illustrated that NVC is partially independent of metabolic signals. In addition, nitric oxide (NO) has been shown in some instances to provide an important mechanism in altering vascular resistance. An extension to the original model of NVC [1] has been developed to include the activation of both somatosensory neurons and GABAergic interneurons and to investigate the role of NO and the delicate balance of GABA and neuronal peptide enzymes (NPY) pathways. The numerical model is compared to murine experimental data that provides time-dependent profiles of oxy, de-oxy, and total-hemoglobin. The results indicate a delicate balance that exists between GABA and NPY when nNOS interneurons are activated mediated by NO. Whereas somatosensory neurons (producing potassium into the extracellular space) do not seem to be effected by the inhibition of NO. Further work will need to be done to investigate the role of NO when stimulation periods are increased substantially from the short pulses of 2 s as used in the above experiments.

The effects of cerebral curvature on cortical spreading depression.

Neuronal activity evokes a localised increase in cerebral blood flow through neurovascular coupling (NVC), a communication system between a group of cells known as a neurovascular unit (NVU). Dysfunctional NVC can lead to pathologies such as cortical spreading depression (CSD), characterised by a slowly propagating wave of neuronal depolarisation and high extracellular potassium (K+) levels. CSD is associated with several neurological disorders such as migraine, stroke, and traumatic brain injury. Insight into the spatial dynamics of CSD in humans is mainly deduced from animal experiments on the smooth lissencephalic brain (in particular murine experiments), however the human cortex is gyrencephalic (highly folded) and is considered likely to exhibit different and more complex patterns of CSD. In this study a large scale numerical NVC model of multiple NVUs is coupled to a vascular tree simulating a two-dimensional cerebral tissue slice. This model is extended with a spatial Gaussian curvature mapping that can simulate the highly folded nature of the human cortex. For a flat surface comparable to a lissencephalic cortex the model can simulate propagating waves of high extracellular K+ travelling radially outwards from a stimulated area at approximately 6.7 mm/min, corresponding well with multiple experimental results. The high K+ concentration induces a corresponding wave of vasoconstriction (with decreased blood flow) then slight vasodilation, achieved through cellular communication within the NVU. The BOLD response decreases below baseline by approximately 10% followed by an increase of 1%. For a surface with spatially varied curvature comparable to a section of gyrencephalic cortex, areas of positive Gaussian curvature inhibit wave propagation due to decreased extracellular diffusion rate. Whereas areas of negative curvature promote propagation. Consequently extracellular K+ is observed travelling as wave segments (as opposed to radial waves) through flat or negatively curved "valleys" corresponding to folds (sulci) in the cortex. If the wave size (defined as the activated area of high K+ concentration) is too small or diffusion rate too low then wave segments can cease propagation. If the diffusion rate is high enough the wave segments can grow from open ends forming loose spiral waves. These results may provide some insight into the differences seen between human and animal experiments.

Integrated models of neurovascular coupling and BOLD signals: Responses for varying neural activations.

A state-of-the-art integrated model of neurovascular coupling (NVC) (Dormanns et al., 2015b; Dormanns et al., 2016; Kenny et al., 2018) and the BOLD response (Mathias et al., 2017a; Mathias et al., 2017b) is presented with the ability to simulate the fMRI BOLD responses due to continuous neuronal spiking, bursting and cortical spreading depression (CSD) along with the underlying complex vascular coupling. Simulated BOLD responses are compared to experimental BOLD signals observed in the rat barrel cortex and in the hippocampus under seizure conditions showing good agreement. Bursting phenomena provides relatively clear BOLD signals as long as the time between bursts is not too short. For short burst periods the BOLD signal remains constant even though the neuron is in a predominantly bursting mode. Simulation of CSD exhibits large negative BOLD signals. Visco-elastic effects of the capillary bed do not seem to have a large effect on the BOLD signal even for relatively high values of oxygen consumption. While the results of the model suggests that potassium ions released during neural activity could act as the main mediator in NVC, it suggests the possibility of other mechanisms that can coexist and increase blood flow such as the arachidonic acid to epoxyeicosatrienoic acid (EET) pathway. The comparison with experimental cerebral blood flow (CBF) data indicates the possible existence of multiple neural pathways influencing the vascular response. Initial negative BOLD signals occur for all simulations due to the rate at which the metabolic oxygen consumption occurs relative to the dilation of the perfusing cerebro-vasculature. However it is unclear as to whether these are normally seen clinically due to the size of the magnetic field. Experimental comparisons for different animal experiments may very well require variation in the model parameters. The complex integrated model is believed to be the first of its kind to simulate both NVC and the resulting BOLD signal.

The role of astrocytic calcium and TRPV4 channels in neurovascular coupling.

Neuronal activity evokes a localised change in cerebral blood flow in a response known as neurovascular coupling (NVC). Although NVC has been widely studied the exact mechanisms that mediate this response remain unclear; in particular the role of astrocytic calcium is controversial. Mathematical modelling can be a useful tool for investigating the contribution of various signalling pathways towards NVC and for analysing the underlying cellular mechanisms. The lumped parameter model of a neurovascular unit with both potassium and nitric oxide (NO) signalling pathways and comprised of neurons, astrocytes, and vascular cells has been extended to include the glutamate induced astrocytic calcium pathway with epoxyeicosatrienoic acid (EET) signalling and the stretch dependent TRPV4 calcium channel on the astrocytic endfoot. Results show that the potassium pathway governs the fast onset of vasodilation while the NO pathway has a delayed response, maintaining dilation longer following neuronal stimulation. Increases in astrocytic calcium concentration via the calcium signalling pathway and/or TRPV4 channel to levels consistent with experimental data are insufficient for inducing either vasodilation or constriction, in contrast to a number of experimental results. It is shown that the astrocyte must depolarise in order to produce a significant potassium flux through the astrocytic BK channel. However astrocytic calcium is shown to strengthen potassium induced NVC by opening the BK channel further, consequently allowing more potassium into the perivascular space. The overall effect is vasodilation with a higher maximal vessel radius.

Macro scale modelling of cortical spreading depression and the role of astrocytic gap junctions.

Neuronal activity evokes a localised increase in cerebral blood flow in a response known as neurovascular coupling (NVC), achieved through communication between a group of cells known as a neurovascular unit (NVU). Dysfunctional NVC can lead to pathologies such as cortical spreading depression (CSD), characterised by a slow moving wave of neuronal depolarisation and high extracellular K+ levels. This phenomenon can be affected by the presence of an astrocytic gap junction network which is able to transport K+ away from areas of high concentrations, however the precise role of these gap junctions remains controversial. In this study, a large scale numerical NVC model of a vascular tree coupled with multiple NVUs comprising a two-dimensional cerebral tissue slice is extended through extracellular K+ and Na+ electrodiffusion and K+ transport via an astrocytic gap junction network. An updated NVU model has been utilised that contains complex neuronal and extracellular dynamics and is able to simulate various pathologies such as CSD and the effect on the vascular response. Under pathological conditions (determined by model parameters) and with extracellular electrodiffusion the model is able to simulate a propagating wave of high extracellular K+ travelling at 6.7 mm/min as can occur in CSD. This wave travels outward from the neuronally stimulated area and is followed by a wave of vasoconstriction (with corresponding decreased blood flow) then slight vasodilation in agreement with multiple experimental results. The vasoconstrictive wave peaks after the K+ wave due to the delayed vascular response. Increasing the density of astrocytic gap junctions reduces the duration and amplitude of the vasoconstrictive wave and for high enough density the vasoconstrictive behaviour outside the stimulated area is eliminated. Gap junctions also reduce the area that is initially affected by vasoconstriction. This in silico model provides a complex and experimentally validated test bed for a variety of neurological phenomena.

Importance of Altered Levels of SERCA, IP3R, and RyR in Vascular Smooth Muscle Cell.

Calcium cycling between the sarcoplasmic reticulum (SR) and the cytosol via the sarco-/endoplasmic reticulum Ca-ATPase (SERCA) pump, inositol-1,4,5-triphosphate receptor (IP3R), and Ryanodine receptor (RyR), plays a major role in agonist-induced intracellular calcium ([Ca2+]cyt) dynamics in vascular smooth muscle cells (VSMC). Levels of these calcium handling proteins in SR get altered under disease conditions. We have developed a mathematical model to understand the significance of altered levels of SERCA, IP3R, and RyR on the intracellular calcium dynamics of VSMC and to understand how variation in protein levels that arise due to diabetes contribute to different VSMC behavior and thus vascular disease. SR is modeled as a single continuous entity with homogeneous intra-SR calcium. Model results show that agonist-induced intracellular calcium dynamics can be modified by changing the levels of SERCA, IP3R, and/or RyR. Lowering SERCA level will enable intracellular calcium oscillations at low agonist concentrations whereas lowered levels of IP3R and RyR need higher agonist concentration for intracellular calcium oscillations. This research suggests that reduced SERCA level is the main factor responsible for the reduced intracellular calcium transients and contractility in VSMCs.

Recruitment Pattern in a Complete Cerebral Arterial Circle.

Blood flow through a vessel depends upon compliance and resistance. Resistance changes dynamically due to vasoconstriction and vasodilation as a result of metabolic activity, thus allowing for more or less flow to a particular area. The structure responsible for directing blood to the different areas of the brain and supplying the increase flow is the cerebral arterial circle (CAC). A series of 1D equations were utilized to model propagating flow and pressure waves from the left ventricle of the heart to the CAC. The focus of the current research was to understand the collateral capability of the circle. This was done by decreasing the peripheral resistance in each of the efferent arteries, up to 10% both unilaterally and bilaterally. The collateral patterns were then analyzed. After the initial 60 simulations, it became apparent that flow could increase beyond the scope of a 10% reduction and still be within in vivo conditions. Simulations with higher percentage decreases were performed such that the same amount of flow increase would be induced through each of the efferent arteries separately, same flow tests (SFTs), as well as those that were found to allow for the maximum flow increase through the stimulated artery, maximum flow tests (MFTs). The collateral pattern depended upon which efferent artery was stimulation and if the stimulation was unilaterally or bilaterally induced. With the same amount of flow increase through each of the efferent arteries, the MCAs (middle cerebral arteries) had the largest impact on the collateral capability of the circle, both unilaterally and bilaterally.

Modeling secondary messenger pathways in neurovascular coupling.

Neurovascular coupling is the well-documented link between neural stimulation and constriction or dilation of the surrounding vasculature. Glial cells mediate this response via their unique anatomy, which connects neurons to arterioles. It is believed that calcium transients and the release of secondary messengers by these cells influence the vascular response. We present a model of intracellular calcium dynamics in an astrocyte (glial cell) and show that stable oscillatory behaviour is possible under certain conditions. We then couple this to a novel model for the relationship between calcium concentration and the production of vasoactive secondary messengers through a fatty-acid intermediate. The two secondary messengers modelled are epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids (EET and 20-HETE, respectively). These secondary messengers are produced on different time scales, and we show how this supports the observation that the vasculature dilates rapidly in response to neural stimulation, before returning to baseline levels on a slower time scale.

Models of neurovascular coupling via potassium and EET signalling.

Functional hyperemia is an important metabolic autoregulation mechanism by which increased neuronal activity is matched by a rapid and regional increase in blood supply. This mechanism is facilitated by a process known as "neurovascular coupling"--the orchestrated communication system involving neurons, astrocytes and arterioles. Important steps in this process are the production of EETs in the astrocyte and the release of potassium, via two potassium channels (BK and KIR), into the perivascular space. We provide a model which successfully accounts for several observations seen in experiment. The model is capable of simulating the approximate 15% arteriolar dilation caused by a 60-s neuronal activation (modelled as a release of potassium and glutamate into the synaptic cleft). This model also successfully emulates the paradoxical experimental finding that vasoconstriction follows vasodilation when the astrocytic calcium concentration (or perivascular potassium concentration) is increased further. We suggest that the interaction of the changing smooth muscle cell membrane potential and the changing potassium-dependent resting potential of the KIR channel are responsible for this effect. Finally, we demonstrate that a well-controlled mechanism of potassium buffering is potentially important for successful neurovascular coupling.

A computational model of hemodynamic parameters in cortical capillary networks.

The analysis of hemodynamic parameters and functional reactivity of cerebral capillaries is still controversial. To assess the hemodynamic parameters in the cortical capillary network, a generic model was created using 2D voronoi tessellation in which each edge represents a capillary segment. This method is capable of creating an appropriate generic model of cerebral capillary network relating to each part of the brain cortex because the geometric model is able to vary the capillary density. The modeling presented here is based on morphometric parameters extracted from physiological data of the human cortex. The pertinent hemodynamic parameters were obtained by numerical simulation based on effective blood viscosity as a function of hematocrit and microvessel diameter, phase separation and plasma skimming effects. The hemodynamic parameters of capillary networks with two different densities (consistent with the variation of the morphometric data in the human cortical capillary network) were analyzed. The results show pertinent hemodynamic parameters for each model. The heterogeneity (coefficient variation) and the mean value of hematocrits, flow rates and velocities of the both network models were specified. The distributions of blood flow throughout the both models seem to confirm the hypothesis in which all capillaries in a cortical network are recruited at rest (normal condition). The results also demonstrate a discrepancy of the network resistance between two models, which are derived from the difference in the number density of capillary segments between the models.

Patterning, integration and characterisation of polymer optical oxygen sensors for microfluidic devices.

This paper describes a process for the layer-by-layer fabrication and integration of luminescent dye-based optical oxygen sensors into microfluidic devices. Application of oxygen-sensitive platinum(ii) octaethylporphyrin ketone fluorescent dye dissolved in polystyrene onto glass substrates by spin-coating was studied. Soft lithography with polydimethylsiloxane (PDMS) stamps and reactive ion etching in oxygen plasma were used to produce sensor patterns with a minimum feature size of 25 microm. Sensors patterns were integrated into a PDMS microfluidic device by plasma bonding. No degradation of the sensor response as a result of the lithography and pattern-transfer processes was detected. Gaseous and dissolved oxygen (DO) detection was characterised using fluorescence microscopy. The intensity signal ratio of the sensor films was found to increase almost two-fold from 3.6 to 6.8 by reducing film thickness from 1.3 microm to 0.6 microm. Calibration of DO measurement showed linear Stern-Volmer behaviour that was constant for flow rates from 0.5 to 2 mL min(-1). The calibrated sensors were subsequently used to demonstrate laterally resolved detection of oxygen inside a microfluidic channel. The fabrication process provides a novel, easy to use method for the repeatable integration of optical oxygen sensors into cell-culture and lab-on-a-chip devices.

Coronary Smooth Muscle Cell Calcium Dynamics: Effects of Bifurcation Angle on Atheroprone Conditions.

This work investigates the effect of arterial bifurcation angulation on atherosclerosis development through in-silico simulations of coupled cell dynamics. The computational model presented here combines cellular pathways, fluid dynamics, and physiologically-realistic vessel geometries as observed in the human vasculature. The coupled cells model includes endothelial cells (ECs) and smooth muscle cells (SMCs) with ion dynamics, hetero and homotypic coupling, as well as electro-diffusive coupling. Three arterial bifurcation surface models were used in the coupled cells simulations. All three simulations showed propagating waves of Ca2+ in both the SMC and EC layers, following the introduction of a luminal agonist, in this case ATP. Immediately following the introduction of ATP concentration Ca2+ waves propagate from the area of high ATP toward the areas of low ATP concentration, forming complex patterns where waves interact with eachother, collide and fade. These dynamic phenomena are repeated with a series of waves of slower velocity. The underlying motivation of this research was to examine the macro-scale phenomena, given that the characteristic length scales of atherosclerotic plaques are much larger than a single cell. The micro-scale dynamics were modeled on macro-scale arterial bifurcation surfaces containing over one million cells. The results of the simulations presented here suggest that susceptibility to atherosclerosis development depends on the bifurcation angulation. In conjunction with findings reported in the literature, the simulation results demonstrate that arterial bifurcations containing wider angles have a more prominent influence on the coupled cells pathways associated with the development of atherosclerosis, by means of disturbed flow and lower SMC Ca2+ concentrations. The discussion of the results considers the findings of this research within the context of the potential link between information transport through frequency encoding of Ca2+ wave dynamics and development of atheroprone conditions.

3D time-varying simulations of Ca2+ dynamics in arterial coupled cells: A massively parallel implementation.

Preferential locations of atherosclerotic plaque are strongly associated with the areas of low wall shear stress and disturbed haemodynamic characteristics such as flow detachment, flow recirculation and oscillatory flow. The areas of low wall shear stress are also associated with the reduced production of adenosine triphosphate in the endothelial layer, as well as the resulting reduced production of inositol trisphosphate (IP3 ). The subsequent variation in Ca2+ signalling and nitric oxide synthesis could lead to the impairment of the atheroprotective function played by nitric oxide. In previous studies, it has been suggested that the reduced IP3 and Ca2+ signalling can explain the correlation of atherosclerosis with induced low WSS and disturbed flow characteristics. The massively parallel implementation described in this article provides insight into the dynamics of coupled smooth muscle cells and endothelial cells mapped onto the surface of an idealised arterial bifurcation. We show that variations in coupling parameters, which model normal and pathological conditions, provide vastly different smooth muscle cell Ca2+ dynamics and wave propagation profiles. The extensibility of the coupled cells model and scalability of the implementation provide a solid framework for in silico investigations of the interaction between complex cellular chemistry and the macro-scale processes determined by fluid dynamics. © 2016 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.

Neurovascular coupling: a parallel implementation.

A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell (SMC) Ca(2+) pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca(2+) in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca(2+) channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca(2+) from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca(2+) in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca(2+) and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks.

Velocity profile method for time varying resistance in minimal cardiovascular system models.

This paper investigates the fluid dynamics governing arterial flow used in lumped parameter cardiovascular system (CVS) models, particularly near the heart where arteries are large. Assumptions made in applying equations conventionally used in lumped parameter models are investigated, specifically that of constant resistance to flow. The Womersley number is used to show that the effects of time varying resistance must be modelled in the pulsatile flow through the large arteries near the heart. It is shown that the equation commonly used to include inertial effects in fluid flow calculations is inappropriate for including time varying resistance. A method of incorporating time varying resistance into a lumped parameter model is developed that uses the Navier-Stokes equations to track the velocity profile. Tests on a single-chamber model show a 17.5% difference in cardiac output for a single-chamber ventricle model when comparing constant resistance models with the velocity profile tracking method modelling time varying resistance. This increase in precision can be achieved using 20 nodes with only twice the computational time required. The method offers a fluid dynamically and physiologically accurate method of calculating large Womersley number pulsatile fluid flows in large arteries around the heart and valves. The proposed velocity profile tracking method can be easily incorporated into existing lumped parameter CVS models, improving their clinical application by increasing their accuracy.

A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function.

The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow-metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging.

Macro-scale phenomena of arterial coupled cells: a massively parallel simulation.

Impaired mass transfer characteristics of blood-borne vasoactive species such as adenosine triphosphate in regions such as an arterial bifurcation have been hypothesized as a prospective mechanism in the aetiology of atherosclerotic lesions. Arterial endothelial cells (ECs) and smooth muscle cells (SMCs) respond differentially to altered local haemodynamics and produce coordinated macro-scale responses via intercellular communication. Using a computationally designed arterial segment comprising large populations of mathematically modelled coupled ECs and SMCs, we investigate their response to spatial gradients of blood-borne agonist concentrations and the effect of micro-scale-driven perturbation on the macro-scale. Altering homocellular (between same cell type) and heterocellular (between different cell types) intercellular coupling, we simulated four cases of normal and pathological arterial segments experiencing an identical gradient in the concentration of the agonist. Results show that the heterocellular calcium (Ca(2+)) coupling between ECs and SMCs is important in eliciting a rapid response when the vessel segment is stimulated by the agonist gradient. In the absence of heterocellular coupling, homocellular Ca(2+) coupling between SMCs is necessary for propagation of Ca(2+) waves from downstream to upstream cells axially. Desynchronized intracellular Ca(2+) oscillations in coupled SMCs are mandatory for this propagation. Upon decoupling the heterocellular membrane potential, the arterial segment looses the inhibitory effect of ECs on the Ca(2+) dynamics of the underlying SMCs. The full system comprises hundreds of thousands of coupled nonlinear ordinary differential equations simulated on the massively parallel Blue Gene architecture. The use of massively parallel computational architectures shows the capability of this approach to address macro-scale phenomena driven by elementary micro-scale components of the system.