Blood Vessel Radius Research Articles

Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma.

Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two-dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three-dimensional light-sheet microscopy. Here, we used the diagnosing immunolabeled paraffin-embedded cleared organs pipeline for tissue clearing, immunolabeling, and three-dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE-1, which targets lymphatic vessels, were examined by calculating three-dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin-fixed paraffin-embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three-dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K-mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High-end tissue clearing techniques and volumetric immunohistochemistry enable three-dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

A lumped parameter model for evaluating coronary artery blood supply capacity.

The coronary artery constitutes a vital vascular system that sustains cardiac function, with its primary role being the conveyance of indispensable nutrients to the myocardial tissue. When coronary artery disease occurs, it will affect the blood supply of the heart and induce myocardial ischemia. Therefore, it is of great significance to numerically simulate the coronary artery and evaluate its blood supply capacity. In this article, the coronary artery lumped parameter model was derived based on the relationship between circuit system parameters and cardiovascular system parameters, and the blood supply capacity of the coronary artery in healthy and stenosis states was studied. The aortic root pressure calculated by the aortic valve fluid-structure interaction (AV FSI) simulator was employed as the inlet boundary condition. To emulate the physiological phenomenon of sudden pressure drops resulting from an abrupt reduction in blood vessel radius, a head loss model was connected at the coronary artery's entrance. For each coronary artery outlet, the symmetric structured tree model was appended to simulate the terminal impedance of the missing downstream coronary arteries. The particle swarm optimization (PSO) algorithm was used to optimize the blood flow viscous resistance, blood flow inertia, and vascular compliance of the coronary artery model. In the stenosis states, the relative flow and fractional flow reserve (FFR) calculated by numerical simulation corresponded to the published literature data. It was anticipated that the proposed model can be readily adapted for clinical application, serving as a valuable reference for diagnosing and treating patients.

Numerical study of blood perfusion and nanoparticle transport in prostate and muscle tumours during intravenous magnetic hyperthermia

In the present work, a two-phase mathematical model of intravenous magnetic (Fe3O4,Fe2O3 or FePt) nanoparticle hyperthermia is considered for the treatment of muscle and prostate tumours. The blood-nanoparticle suspension is described as a non-Newtonian (Quemada) nanofluid, and the effects of thermophoresis and Brownian motion are considered. The blood vessel region is surrounded by a cancerous (muscle or prostate) tumour region, a non-cancerous (muscle or prostate) region and a fat layer. Heat is generated within these tissue regions using an external alternating magnetic field. A numerical solution of the problem is obtained using the mixed finite element method with P2-P1 Taylor-Hood elements. Using this numerical solution, the influence of tumour size, blood vessel radius and haematocrit on blood flow, convective heat transfer, nanoparticle mass transport and blood pressure is examined.

Physiological model using diffuse reflectance spectroscopy for nonmelanoma skin cancer diagnosis.

Diffuse reflectance spectroscopy (DRS) is a noninvasive, fast, and low-cost technology with potential to assist cancer diagnosis. The goal of this study was to test the capability of our physiological model, a computational Monte Carlo lookup table inverse model, for nonmelanoma skin cancer diagnosis. We applied this model on a clinical DRS dataset to extract scattering parameters, blood volume fraction, oxygen saturation and vessel radius. We found that the model was able to capture physiological information relevant to skin cancer. We used the extracted parameters to classify (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]) vs actinic keratosis (AK) and (BCC, SCC, AK) vs normal. The area under the receiver operating characteristic curve achieved by the classifiers trained on the parameters extracted using the physiological model is comparable to that of classifiers trained on features extracted via Principal Component Analysis. Our findings suggest that DRS can reveal physiologic characteristics of skin and this physiologic model offers greater flexibility for diagnosing skin cancer than a pure statistical analysis. Physiological parameters extracted from diffuse reflectance spectra data for nonmelanoma skin cancer diagnosis.

Influence of Blood Vessels on Temperature during High-Intensity Focused Ultrasound Hyperthermia Based on the Thermal Wave Model of Bioheat Transfer

The coupled effects of blood vessels and thermal relaxation time on temperature and thermal lesion region in biological tissue during high-intensity focused ultrasound (HIFU) hyperthermia are numerically investigated. Considering the non-Fourier behavior of heat conduction in biological tissue, the traditional Pennes bioheat equation was modified to thermal wave model of bioheat transfer (TWMBT). Consequently, a joint physical model, which combines TWMBT for tissue and energy transport equation for blood vessel, is presented to predict the evolution of temperature and the thermal lesion region. In this study, pulsatile blood flow is first introduced into numerical study of HIFU hyperthermia, and thermal relaxation time, ultrasonic focus location, blood vessel radius, and blood flow velocity are all taken into account. The results show that the thermal relaxation time plays a key role in the temperature and the thermal lesion region. Larger thermal relaxation time results in lower temperature and smaller thermal lesion region, which indicates that TWMBT leads to lower temperature and smaller thermal lesion region compared to Pennes bioheat transfer model. In addition, we found that the ultrasonic focus location and blood vessel radius significantly affected the temperature and thermal lesion region, while the heartbeat frequency and amplitude factor of pulsating blood flow as well as the average velocity of blood flow had only a slight effect.

Early increase in blood supply (EIBS) is associated with tumor risk in the Azoxymethane model of colon cancer

BackgroundThe present study aimed to investigate the role of blood supply in early tumorigenesis in colorectal cancer. We leveraged the renin angiotensin system (RAS) to alter colonic blood supply and determine the effect on tumor initiation and progression.MethodsTo test the effect of blood supply on tumorigenesis, 53 male A/J mice were randomly assigned to one of three RAS modulation groups and one of two AOM treatments. The RAS modulation groups were I) water (RAS-unmodulated) as a control group, II) angiotensin-II and III) the angiotensin receptor blocker, Losartan. The mice in each group were then randomly split into either the saline control condition or the AOM-treated condition in which tumors were induced with a standard protocol of serial azoxymethane (AOM) injections. To monitor microvascular changes in the rectal mucosa during the study, we used confocal laser endomicroscopy (CLE) with FITC-Dextran for in-vivo imaging of vessels and polarization-gated spectroscopy (PGS) to quantify rectal hemoglobin concentration ([Hb]) and blood vessel radius (BVR).ResultsAt 12 weeks post-AOM injections and before tumor formation, CLE images revealed many traditional hallmarks of angiogenesis including vessel dilation, loss of co-planarity, irregularity, and vessel sprouting in the pericryptal capillaries of the rectal mucosa in AOM-Water tumor bearing mice. PGS measurements at the same time-point showed increased rectal [Hb] and decreased BVR. At later time points, CLE images showed pronounced angiogenic features including irregular networks throughout the colon. Notably, the AOM-Losartan mice had significantly lower tumor multiplicity and did not exhibit the same angiogenic features observed with CLE, or the increase in [Hb] or decrease in BVR measured with PGS. The AOM-AngII mice did not have any significant trends.ConclusionIn-vivo PGS measurements of rectal colonic blood supply as well as CLE imaging revealed angiogenic disruptions to the capillary network prior to tumor formation. Losartan demonstrated an effective way to mitigate the changes to blood supply during tumorigenesis and reduce tumor multiplicity. These effects can be used in future studies to understand the early vessel changes observed.

Pressure and wall shear stress in blood hammer – Analytical theory

We describe an analytical theory of blood hammer in a long and stiffened artery due to sudden blockage. Based on the model of a viscous fluid in laminar flow, we derive explicit expressions of oscillatory pressure and wall shear stress. To examine the effects on local plaque formation we also allow the blood vessel radius to be slightly nonuniform. Without resorting to discrete computation, the asymptotic method of multiple scales is utilized to deal with the sharp contrast of time scales. The effects of plaque and blocking time on blood pressure and wall shear stress are studied. The theory is validated by comparison with existing water hammer experiments.

Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill.

It has been hypothesized that continuously releasing drug molecules into the tumor over an extended period of time may significantly improve the chemotherapeutic efficacy by overcoming physical transport limitations of conventional bolus drug treatment. In this paper, we present a generalized space- and time-dependent mathematical model of drug transport and drug-cell interactions to quantitatively formulate this hypothesis. Model parameters describe: perfusion and tissue architecture (blood volume fraction and blood vessel radius); diffusion penetration distance of drug (i.e., a function of tissue compactness and drug uptake rates by tumor cells); and cell death rates (as function of history of drug uptake). We performed preliminary testing and validation of the mathematical model using in vivo experiments with different drug delivery methods on a breast cancer mouse model. Experimental data demonstrated a 3-fold increase in response using nano-vectored drug vs. free drug delivery, in excellent quantitative agreement with the model predictions. Our model results implicate that therapeutically targeting blood volume fraction, e.g., through vascular normalization, would achieve a better outcome due to enhanced drug delivery.Author SummaryCancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly, this model only requires a limited number of parameters which can all be readily assessed from standard clinical diagnostic measurements (e.g., histopathology and CT). This addresses an important challenge in current translational research and justifies further development of the model towards clinical translation.

Predictive Modeling of Drug Response in Non-Hodgkin's Lymphoma.

We combine mathematical modeling with experiments in living mice to quantify the relative roles of intrinsic cellular vs. tissue-scale physiological contributors to chemotherapy drug resistance, which are difficult to understand solely through experimentation. Experiments in cell culture and in mice with drug-sensitive (Eµ-myc/Arf-/-) and drug-resistant (Eµ-myc/p53-/-) lymphoma cell lines were conducted to calibrate and validate a mechanistic mathematical model. Inputs to inform the model include tumor drug transport characteristics, such as blood volume fraction, average geometric mean blood vessel radius, drug diffusion penetration distance, and drug response in cell culture. Model results show that the drug response in mice, represented by the fraction of dead tumor volume, can be reliably predicted from these inputs. Hence, a proof-of-principle for predictive quantification of lymphoma drug therapy was established based on both cellular and tissue-scale physiological contributions. We further demonstrate that, if the in vitro cytotoxic response of a specific cancer cell line under chemotherapy is known, the model is then able to predict the treatment efficacy in vivo. Lastly, tissue blood volume fraction was determined to be the most sensitive model parameter and a primary contributor to drug resistance.

Development of a diffusion-based mathematical model for predicting chemotherapy effects.

Mathematical modeling of drug transport can complement current experimental and clinical investigations to understand drug resistance mechanisms, which eventually will help to develop patient-specific chemotherapy treatments. In this paper, we present a general time- and space-dependent mathematical model based on diffusion theory for predicting chemotherapy outcome. This model has two important parameters: the blood volume fraction and radius of blood vessels divided by drug diffusion penetration length. Model analysis finds that a larger ratio of the radius of blood vessel to diffusion penetration length resulted in to a larger fraction of tumor killed, thereby leading to a better treatment outcome. Clinical translation of the model can help quantify and predict the optimal dosage size and frequency of chemotherapy for individual patients.

Polarization gating spectroscopy of normal-appearing duodenal mucosa to detect pancreatic cancer

According to the field effect theory, by detecting microvasculature changes such as early increase in blood supply (EIBS) in the surrounding tissue, neoplastic lesions can be identified from a distance. To determine the feasibility and efficacy of a fiberoptic probe containing novel polarization gating spectroscopy technology to identify patients with pancreatic adenocarcinoma (PAC) by the field effect theory. Prospective cohort (pilot) study. Outpatient tertiary care center. Adult (≥ 18 years) patients undergoing EGD-EUS were screened. Patients with PAC were included in the "cancer" group and patients without PAC were included in the "control" group. We excluded patients with other known malignancies and gastroduodenal premalignant lesions. Spectroscopic measurements of EIBS variables, such as deoxyhemoglobin concentration (DHb) and mean blood vessel radius (BVR), were obtained from 5 periampullary locations. The Mann-Whitney rank sum test was used for the statistical analysis (P ≤ .05). Fourteen patients (mean age 72 years, 79% male) in the cancer group and 15 patients (mean age 63 years, 60% male) in the control group were included in the final analysis. At the ampullary site, both DHb (P = .001) and BVR (P = .03) were higher in PAC patients than in the control subjects. The DHb alone (92% sensitivity, 86% specificity) or in combination with BVR (92% sensitivity, 79% specificity) can differentiate PAC from control subjects with high accuracy. Small sample size, unmatched control subjects. Spectroscopic measurements of EIBS by fiberoptic probes are feasible. Preliminary evidence suggests that in vivo measurement of normal-appearing duodenal tissue can differentiate PAC patients from a distance with high accuracy.

Microhemodynamic parameters quantification from intravital microscopy videos

Blood flow and blood–endothelium interactions correspond with the genesis of cardiovascular diseases. Therefore, quantitative analysis of blood flow dynamics at the microcirculation level is of special interest. Regulatory mechanisms mediated by blow flow have been studied in detail using in vitro approaches. However, these mechanisms have not been fully validated in vivo due to technical limitations that arise when quantifying microhemodynamics with the required level of detail. Intravital microscopy combined with high-speed video recordings has been used for the analysis of blood flow in small blood vessels of chronic and acute experimental tissue preparations. This tool can be used to study the interaction between the flowing blood and the vessel walls of arterioles and venules with sufficient temporal and spatial resolution. Our objective was to develop a simple and robust cross-correlation algorithm for the automatic analysis of high-speed video recordings of microcirculatory blood flow. The algorithm was validated using in vitro and in vivo systems. Results indicate that the algorithm's ability to estimate the velocity of local red blood cells as a function of blood vessel radius is highly accurate. They thereby suggest that the algorithm could be used to explore dynamic changes in blood flow under different experimental conditions including a wide range of flow rates and hematocrit levels. The algorithm can also be used to measure volumetric flow rates, radial velocity profiles, wall shear rate, and wall shear stress. Several applications are presently explored, including the analysis of velocity profiles in the branches of arterial bifurcations. This work demonstrates the robustness of the cross-correlation technique in various flow conditions and elucidates its potential application for in vivo determination of blood flow dynamics in the microcirculation.

Pressure distribution and wall shear stress in stenosis and abdominal aortic aneurysm by computational fluid dynamics modeling (CFD)

sThe models of stenosed blood vessel with three different types of stenosis types have been modeled to investigate blood flow characteristics. The study was performed to investigate various hemodynamics, such as pressure and wall shear stress (WSS), with the change of stenosis ratio and Reynolds numbers (Re). The results of modeling, the minimum WSS occurred in different regions according to the stenosis types. The change of the diameter of blood vessel showed up in the pre-stenotic region by elastic behavior characteristics of blood vessels. Also, when the thickness of wall of blood vessel is 2 mm, the radius of blood vessel is increased by approximately two-times. As atherosclerosis progresses, the wall of blood vessels gradually loses elasticity and then the thickness of blood vessels gets thinner.

Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans

We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.

Monitoring the Longitudinal Intra-tumor Physiological Impulse Response to VEGFR2 Blockade in Breast Tumors Using DCE-CT

The purpose of this study was to quantify and model the longitudinal intra-tumor physiological response to a single dose of a monoclonal antibody specific to the VEGFR2 using dynamic contrast-enhanced CT. Dynamic contrast-enhanced CT imaging was performed on athymic nude mice bearing xenograft VEGF-transfected MCF-7 tumors (MCF7(VEGF)) to quantify intra-tumor physiology pre- and post-injection (days 2, 7, and 14) of a nonspecific (IgG1, controls) and specific (DC101, treated) monoclonal antibody targeting VEGFR2. Parametrical maps of tumor physiology-perfusion (F), permeability surface area (PS), fractional plasma (f(p)), and interstitial space (f (is))-were obtained at four time points over a 2-week period. A temporal multistage recovery process whereby a decoupling of the fractional change in physiological parameters (f (p), F) was observed when comparing treated to control tumors: f (p) and perfusion decreased by a combined 27% (P < 0.01) and 65% (P < 0.01) on day 2, while only perfusion remained reduced by 46% (P < 0.01) on day 7. Intra-tumor heterogeneity defined by the change in variance of perfusion decreased on days 2 and 7; no change in the variance of f(p) was observed. Analysis based on a mathematical model linking perfusion and vascular morphology indicates that a decrease in f(p) and perfusion was consistent with a reduction in blood vessel radius, followed by an increase in the vascular radius and tortuosity resulting in the decoupling of f(p) and perfusion before returning to control levels. Inhibiting VEGFR2 activity results in a temporal decoupling of physiological parameters, which can be explained by a combination of morphological changes influencing perfusion. Such a decoupling has the potential to significantly impact the delivery of pharmaceuticals and oxygen within solid tumors, critical factors in combined anti-angiogenic and radio- and chemotherapies.

GPCR signalling in hypertension: role of GRKs

Hypertension is a prevalent condition in the developed world and disease severity is directly correlated with additional cardiovascular complications. It is estimated that 30% of the adult population in the United States has hypertension, which is classified as a systolic blood pressure > or =140 mmHg and/or a diastolic blood pressure > or =90 mmHg. A prolonged increase in afterload ultimately leads to congestive heart failure in the majority of cases. Currently, medication designed to treat hypertension is inadequate, thus new therapies need to be explored. Blood pressure is tightly regulated by blood vessel radius, which is established by hormones and/or peptides binding to GPCRs (G-protein-coupled receptors). Catecholamines and peptide hormones, such as AngII (angiotensin II), are elevated in hypertension and, therefore, signalling by these GPCRs is increased. Their signalling is tightly controlled by a class of proteins, the GRKs (GPCR kinases). Elevated levels of either GRK2 or GRK5 in both the lymphocytes and VSM (vascular smooth muscle) are associated with human hypertension and animal models of the disease. The focus of the present review is on the role GRKs, and their regulation of GPCRs, play in high blood pressure.

The Effect of Adventitia Stripping in Refractory Ischemic Digits

Ischemic disease of digits is a very frustrating and extremely difficult clinical problem. It is often caused by a variety of diseases, such as atherosclerosis, connective tissue disease, trauma and Raynaud's disease. Patients with this problem usually suffer from poor tissue perfusion and impaired microcirculation. In clinical, ischemic digits often present with pain, cold intolerance, ulceration and even gangrene change. Many strategies are proposed today to overcome this disease. Behavioral therapies, such as avoidance of cold exposure and smoking are a very important intervention. Pharmacologic therapies, like the administration of calcium channel blocker, PGE1 and other vasodilators have been the most commonly used agents. Sympatholytic drugs have also been added to reduce the sympathetic tone in vascular smooth muscles. In addition, anticoagulants or antiplatelet agents are administered to inhibit thrombus formation in occlusive vascular disease. Although these agents are usually effective, unfortunately, in refractory cases, amputation is unavoidable. Those patients have to suffer the fate of partial or total loss of the digits. This ultimate outcome frequently comes with high morbidity and dysfunctions both in physical and psychological terms. In those cases which are refractory to medical therapy, surgical intervention had been carried out to improve tissue perfusion. Tissue perfusion depends on the integrity of the vasculature and the neurovascular regulatory elements. Historically, microsurgical revascularization and sympathectomy were widely performed to recover adequate blood flow. Microvascular reconstruction with interposition vein grafting can be used to reestablish the vascular structure. However, not all cases with digital ischemia are suitable for this procedure due to the possible occurrence of multifocal stenosis. Sympathectomy can reduce sympathetic tone and thus increase the radius of blood vessel. According to Poiseuille's law, blood flow is directly proportional to the fourth power of the vessel's radius. So even a small increase of radius of blood vessel can lead to a very great increase in blood flow. According to Pick and Flatt, sympathetic fibers travel along the epineurium of peripheral nerve, pass to the adventitia, and innervate the smooth muscle of vessels. The removal of adventitia can block the sympathetic tone in the smooth muscle. This procedure may also increase the radius of vessel and reestablish adequate blood flow.

Shear stress modulates vasopressin-induced renal vasoconstriction in rats.

Vasopressin is a potent renal vasoconstrictor in vitro which elicits relatively minor renal vascular effects in vivo. Efficient modulation might occur through shear stress-elicited release of vasodilator compounds from endothelial cells. The aim of this study was to evaluate in vitro, in the isolated perfused kidney, the influence of shear stress and related nitric oxide (NO) release on basal renal vascular tone and on vasopressin-induced renal vasoconstriction. Rat kidneys were perfused at a constant flow rate of 8 ml/min with Tyrode's solution (relative viscosity eta=1) or, in order to increase shear stress, with Tyrode's solution supplemented with 4.7% Ficoll 400 (Ficoll 400; eta=2.3), which is representative of the relative viscosity found in small vessels. Renal shear stress was further elevated during vasoconstriction elicited by vasopressin. Basal renal true vascular conductance, which reflects mean blood vessel radius, was 2.5-fold higher and overall wall shear stress doubled in Ficoll 400 - as compared to Tyrode-perfused kidneys. The decrease in vascular conductance elicited by NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) increased with the viscosity of the perfusate. Shear stress was elevated during vasopressin-induced renal vasoconstriction, all the more kidneys were Ficoll 400-perfused. In these kidneys, the concentration-response curve to vasopressin was shifted to the right, giving evidence of hyporeactivity to the peptide. L-NNA potentiated vasoconstriction to vasopressin particularly in Ficoll 400-perfused kidneys, although additional inhibition of cyclooxygenase and/or cytochrome P(450) was without effect. These results provide in vitro evidence that shear stress enhanced by perfusate viscosity increases basal renal vascular conductance by an NO-dependent mechanism. Together with shear stress enhanced during vasoconstriction, it blunts vasopressin-induced renal vasoconstriction.

Free nitric oxide diffusion in the bronchial microcirculation.

Theoretical mass transfer rates and concentration distributions were determined for transient diffusion of free nitric oxide (NO) generated in vivo from vascular endothelial cells. Our analytical framework is typical of the bronchial circulation in the human pulmonary system but is applicable to the microvascular circulation in general. We characterized mass transfer rates in terms of the fractional mass flux across a boundary relative to the total endothelial NO production rate. NO concentration in the tissue surrounding blood vessels was expressed in terms of fractional soluble guanylate cyclase (sGC) activity. Our results suggest that endothelium-derived free NO is capable of vascular smooth muscle dilation despite its rapid consumption by hemoglobin in blood. An optimal blood vessel radius of 20 microm was estimated for NO signaling. We hypothesize intermittent generation of endothelial NO as a possible mechanism for sGC activation in vascular smooth muscle. This mechanism enhances the efficacy of NO-modulated vascular smooth muscle dilation while minimizing NO losses to blood and surrounding tissue.

STRESS CONCENTRATION DUE TO ADVANCING HEART PULSE THROUGH A BLOOD VESSEL JOINT

The effect of a vessel joint of different properties on the heart pulse propagation and anastomosis junction is investigated. The system under consideration is modelled by an elastic piecewise-constant vessel consisting of two perfectly jointed vessels of different thicknesses and radii. A mathematical model is developed, to perform numerical calculations and to obtain some qualitative and quantitative estimations. The effect of different thicknesses and radii of jointed blood vessels on the concentrations of pressure, radial vessel wall displacement, bending moments and shear forces are analyzed in detail.