Preload dependence in an animal model of mild heart failure with preserved ejection fraction (HFpEF).

AIM: Heart Failure with preserved Ejection Fraction (HFpEF) is characterized by diastolic dysfunction and reduced cardiac output, but its pathophysiology remains poorly understood. Animal models of HFpEF are challenging due to difficulties in assessing the degree of heart failure in small animals. This study aimed at inducing HFpEF in a mouse model to probe preload-dependency. METHODS: Increased body mass and arterial hypertension were induced in mice using a Western diet and NO synthase inhibition. Preload dependence was tested ex vivo. RESULTS: Mice with obesity and hypertension exhibited reduced cardiac output, indicating a failing heart. Increased left ventricular filling pressure during diastole suggested reduced compliance. Notably, the ejection fraction was preserved, suggesting the development of HFpEF. Spontaneous physical activity at night was reduced in HFpEF mice, indicating exercise intolerance; however, the cardiac connective tissue content was comparable between HFpEF and control mice. The HFpEF mice showed increased vulnerability to reduced preload ex vivo, indicating that elevated left ventricular filling pressure compensated for the rigid left ventricle, preventing a critical decrease in cardiac output. CONCLUSION: This animal model successfully developed mild HFpEF with a reduced pump function that was dependent on a high preload. A model of mild HFpEF may serve as a valuable tool for studying disease progression and interventions aimed at delaying or reversing symptom advancement, considering the slow development of HFpEF in patients.

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.

Histological Analyses of Capsular Contracture and Associated Risk Factors: A Systematic Review.

BACKGROUND: Capsular contracture is a severe complication to breast surgery with implants. Previous studies suggest multiple risk factors are associated with capsular contracture, but the etiology is still unknown. We performed a literature review to investigate existing studies on histological analyses of breast implant capsules and how clinical risk factors impact the capsule morphology. METHODS: The literature search was conducted in PubMed. Studies that performed histological analyses of breast implant capsules were included. Animal studies or studies with a study population of less than five patients were excluded. RESULTS: Fifty-two studies were included. The histological analyses showed that the breast implant capsules were organized in multiple layers with an inner layer of synovial-like metaplasia which was reported to diminish in capsules with capsular contracture. The remaining layers of the capsule mostly consisted of collagen. The alignment of the collagen fibers differed between contracted and non-contracted capsules, and capsules with higher Baker grade were generally thickest and contained more tissue inflammation. Studies investigating capsules affected by radiotherapy found a more pronounced inflammatory response and the capsules were generally thicker and fibrotic compared with nonirradiated capsules. CONCLUSIONS: The included studies offer valuable insights into the histological changes caused by capsular contracture and their relation to clinical risk factors. Further studies with larger sample sizes and more strict inclusion criteria are needed to further investigate implant capsules and the role of the synovial-like metaplasia for the development of capsular contracture. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 .

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.

Stimulation history affects vasomotor responses in rat mesenteric arterioles.

Resistance vessels regulate blood flow by continuously adjusting activity of the wall smooth muscle cells. These cells integrate a variety of stimuli from blood, endothelium, autonomic nerves, and surrounding tissues. Each stimulus elicits an intracellular signaling cascade that eventually influences activation of the contractile machinery. The characteristic time scale of each cascade and the sharing of specific reactions between cascades provide for complex behavior when a vessel receives multiple stimuli. Here, we apply sequential stimulation with invariant concentrations of vasoconstrictor (norepinephrine/methoxamine) and vasodilator (SNAP/carbacol) to rat mesenteric vessels in the wire myograph to show that (1) time elapsed between addition of two vasoactive drugs and (2) the sequence of addition may significantly affect final force development. Furthermore, force oscillations (vasomotion) often appear upon norepinephrine administration. Using computational modeling in combination with nitric oxide (NO) inhibition/NO addition experiments, we show that (3) amplitude and number of oscillating vessels increase over time, (4) the ability of NO to induce vasomotion depends on whether it is applied before or after norepinephrine, and (5) emergence of vasomotion depends on the prior dynamical state of the system; in simulations, this phenomenon appears as "hysteresis." These findings underscore the time-dependent nature of vascular tone generation which must be considered when evaluating the vasomotor effects of multiple, simultaneous stimuli in vitro or in vivo.

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.

Rat retinal vasomotion assessed by laser speckle imaging.

Vasomotion is spontaneous or induced rhythmic changes in vascular tone or vessel diameter that lead to rhythmic changes in flow. While the vascular research community debates the physiological and pathophysiological consequence of vasomotion, there is a great need for experimental techniques that can address the role and dynamical properties of vasomotion in vivo. We apply laser speckle imaging to study spontaneous and drug induced vasomotion in retinal network of anesthetized rats. The results reveal a wide variety of dynamical patterns. Wavelet-based analysis shows that (i) spontaneous vasomotion occurs in anesthetized animals and (ii) vasomotion can be initiated by systemic administration of the thromboxane analogue U-46619 and the nitric-oxide donor S-nitroso-acetylDL-penicillamine (SNAP). Although these drugs activate different cellular pathways responsible for vasomotion, our approach can track the dynamical changes they cause.

Laser speckle analysis of retinal vascular dynamics.

Studies of vascular responses are usually performed on isolated vessels or on single vessels in vivo. This allows for precise measurements of diameter or blood flow. However, dynamical responses of the whole microvascular network are difficult to access experimentally. We suggest to use full-field laser speckle imaging to evaluate vascular responses of the retinal network. Image segmentation and vessel recognition algorithms together with response mapping allow us to analyze diameter changes and blood flow responses in the intact retinal network upon systemic administration of the vasoconstrictor angiotensin II, the vasodilator acetylcholine or on the changing level of anesthesia in in vivo rat preparations.

Vascular flow reserve as a link between long-term blood pressure level and physical performance capacity in mammals.

Mean arterial pressure (MAP) is surprisingly similar across different species of mammals, and it is, in general, not known which factors determine the arterial pressure level. Mammals often have a pronounced capacity for sustained physical performance. This capacity depends on the vasculature having a flow reserve that comes into play as tissue metabolism increases. We hypothesize that microvascular properties allowing for a large vascular flow reserve is linked to the level of the arterial pressure.To study the interaction between network properties and network inlet pressure, we developed a generic and parsimonious computational model of a bifurcating microvascular network where diameter and growth of each vessel evolves in response to changes in biomechanical stresses. During a simulation, the network develops well-defined arterial and venous vessel characteristics. A change in endothelial function producing a high precapillary resistance and thus a high vascular flow reserve is associated with an increase in network inlet pressure. Assuming that network properties are independent of body mass, and that inlet pressure of the microvascular network is a proxy for arterial pressure, the study provides a conceptual explanation of why high performing animals tend to have a high MAP.

Influence of Connexin40 on the renal myogenic response in murine afferent arterioles.

Renal autoregulation consists of two main mechanisms; the myogenic response and the tubuloglomerular feedback mechanism (TGF). Increases in renal perfusion pressure activate both mechanisms causing a reduction in diameter of the afferent arteriole (AA) resulting in stabilization of the glomerular pressure. It has previously been shown that connexin-40 (Cx40) is essential in the renal autoregulation and mediates the TGF mechanism. The aim of this study was to characterize the myogenic properties of the AA in wild-type and connexin-40 knockout (Cx40KO) mice using both in situ diameter measurements and modeling. We hypothesized that absence of Cx40 would not per se affect myogenic properties as Cx40 is expressed primarily in the endothelium and as the myogenic response is known to be present also in isolated, endothelium-denuded vessels. Methods used were the isolated perfused juxtamedullary nephron preparation to allow diameter measurements of the AA. A simple mathematical model of the myogenic response based on experimental parameters was implemented. Our findings show that the myogenic response is completely preserved in the AA of the Cx40KO and if anything, the stress sensitivity of the smooth muscle cell in the vascular wall is increased rather than reduced as compared to the WT. These findings are compatible with the view of the myogenic response being primarily a local response to the local transmural pressure.

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.

Gap junctions suppress electrical but not [Ca(2+)] heterogeneity in resistance arteries.

Despite stochastic variation in the molecular composition and morphology of individual smooth muscle and endothelial cells, the membrane potential along intact microvessels is remarkably uniform. This is crucial for coordinated vasomotor responses. To investigate how this electrical homogeneity arises, a virtual arteriole was developed that introduces variation in the activities of ion-transport proteins between cells. By varying the level of heterogeneity and subpopulations of gap junctions (GJs), the resulting simulations shows that GJs suppress electrical variation but can only reduce cytosolic [Ca(2+)] variation. The process of electrical smoothing, however, introduces an energetic cost due to permanent currents, one which is proportional to the level of heterogeneity. This cost is particularly large when electrochemically different endothelial-cell and smooth-muscle-cell layers are coupled. Collectively, we show that homocellular GJs in a passively open state are crucial for electrical uniformity within the given cell layer, but homogenization may be limited by biophysical or energetic constraints. Owing to the ubiquitous presence of ion transport-proteins and cell-cell heterogeneity in biological tissues, these findings generalize across most biological fields.

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.

Transurethral microwave thermotherapy treatment of chronic urinary retention in patients unsuitable for surgery.

OBJECTIVE: The aim of this study was to evaluate transurethral microwave thermotherapy (TUMT) in the treatment of chronic urinary retention due to benign prostatic hyperplasia (BPH) in patients unsuitable for surgery. MATERIAL AND METHODS: The study enrolled 124 patients with chronic urinary retention due to BPH. The median age was 80 years (61-92 years). Of the enrolled patients, 77 (62%) were assessed by an anaesthesiologist as being unsuitable for surgery owing to cardiac, pulmonary, neurological or other diseases. Overall, 115 patients (93%) had an indwelling catheter. The remaining nine patients (7%) performed clean intermittent self-catheterization. The treatment was performed under local anaesthesia in the outpatient department using the ProstaLund Coretherm Device. At the 6-month follow-up, the Danish version of the International Prostate Symptom Score (DAN-PSS), postvoiding residual volume and urinary peak flow were measured. Improvement in quality of life was also registered. RESULTS: The success of TUMT was assessed by looking at the percentage of patients relieved of their catheter and by the improvement in quality of life. Overall, 77% of patients were relieved of their catheter and 79% reported an improvement in their quality of life. CONCLUSION: In this study, both the median age and the percentage of patients unsuitable for surgery were larger than in previous studies. Despite this, TUMT relieved 77% of their catheter and 79% reported an improvement in their quality of life. This study shows that TUMT is an effective treatment for patients unsuitable for surgery and with chronic urinary retention.

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.