Structural response of microcirculatory networks to changes in demand: information transfer by shear stress

Matching blood flow to metabolic demand in terminal vascular beds involves coordinated changes in diameters of vessels along flow pathways, requiring upstream and downstream transfer of information on local conditions. Here, the role of information transfer mechanisms in structural adaptation of microvascular networks after a small change in capillary oxygen demand was studied using a theoretical model. The model includes diameter adaptation and information transfer via vascular reactions to wall shear stress, transmural pressure, and oxygen levels. Information transfer is additionally effected by conduction along vessel walls and by convection of metabolites. The model permits selective blocking of information transfer mechanisms. Six networks, based on in vivo data, were considered. With information transfer, increases in network conductance and capillary oxygen supply were amplified by factors of 4.9 +/- 0.2 and 9.4 +/- 1.1 (means +/- SE), relative to increases when information transfer was blocked. Information transfer by flow coupling alone, in which increased shear stress triggers vascular enlargement, gave amplifications of 4.0 +/- 0.3 and 4.9 +/- 0.5. Other information transfer mechanisms acting alone gave amplifications below 1.6. Thus shear-stress-mediated flow coupling is the main mechanism for the structural adjustment of feeding and draining vessel diameters to small changes in capillary oxygen demand.     

Blood flow regulation in the cerebral microvasculature with an arcadal network: a numerical simulation

Blood flow regulation in the cerebral microvasculature with an arcadal network was investigated using a numerical simulation. A mathematical model for blood flow in the arcadal network, based on in vivo data of cat cerebral microvasculature and flow velocity was developed. The network model consists of 45 vessel segments and 25 branching points. To simulate microvascular response to blood flow, non-reactive (solid), cerebral arteriole-like, or skeletal muscle arteriole-like responses to wall shear stress were taken into account. Numerical calculation was carried out in the flow condition where the inlet (arterial) pressure was changed from 60 to 120 mmHg. Flow-rate in each efferent vessel and the mean flow-rate over all efferent vessels were evaluated for assessment of blood supply to the local area of cerebral tissue. The simulation demonstrated the wall shear stress-induced vasodilation in the arcadal network worked to maintain the blood flow at a constant level with pressure variable in a wide range. It is suggested that an individual microvessel (segment) should join in the regulatory process of flow, interacting with other microvessels (cooperative regulation).     

Structural remodeling of mouse gracilis artery after chronic alteration in blood supply

The goals of this study were to determine the time course and spatial dependence of structural diameter changes in the mouse gracilis artery after a redistribution of blood flow and to compare the observations with predictions of computational models for structural adaptation. Diameters were measured 1, 2, 7, 14, 21, 28, and 56 days after resection of one of the two blood supplies to the artery. Overall average diameter, normalized with respect to diameters in untreated vessels, increased slightly during the first 7 days, then increased more rapidly, reaching a peak around day 21, and then decreased. This transient increase in diameter was spatially nonuniform, being largest toward the point of resection. A previously developed theoretical model, in which diameter varies in response to stimuli derived from local metabolic and hemodynamic conditions, was extended to include effects of time-delayed remodeling stimuli in regions of reduced perfusion. Predictions of this model were consistent with observed diameter changes, including the transient increase in diameters near the point of resection, when a remodeling stimulus with a time delay of approximately 7 days was included. The results suggest that delayed stimuli significantly influence the dynamic characteristics of vascular remodeling resulting from reduced blood supply.     

Integrative control of the skeletal muscle microcirculation in the maintenance of arterial pressure during exercise.

Skeletal muscle blood flow and vascular conductance are influenced by numerous factors that can be divided into two general categories: central cardiovascular control mechanisms and local vascular control mechanisms. Central cardiovascular control mechanisms are thought to be designed primarily for the maintenance of arterial pressure and central cardiovascular homeostasis, whereas local vascular control mechanisms are thought to be designed primarily for the maintenance of muscle homeostasis. To support the high metabolic rates that can be generated during muscle contraction, skeletal muscle has a tremendous capacity to vasodilate and increase oxygen and nutrient delivery. During whole body dynamic exercise at maximal oxygen consumption (VO2 max), the skeletal muscle receives 85-90% of cardiac output. Yet despite receiving such a large fraction of cardiac output during high-intensity exercise, a vasodilator reserve remains with the potential to produce further elevations in skeletal muscle vascular conductance and blood flow. However, because maximal cardiac output is reached during exercise at VO2 max, further elevations in muscle vascular conductance would produce a fall in arterial pressure. Therefore, limits on muscle perfusion must be imposed during whole body exercise to prevent such drops in pressure. Effective arterial pressure control in response to a potentially hypotensive challenge during high-intensity exercise occurs primarily through reflex-mediated increases in sympathetic nerve activity, which are capable of modulating vasomotor tone of the skeletal muscle resistance vasculature. Thus skeletal muscle vascular conductance and perfusion are primarily mediated by local factors at rest and during exercise, but other centrally mediated control systems are superimposed on the dominant local control mechanisms to provide an integrated regulation of both arterial pressure and skeletal muscle vascular conductance and perfusion during whole body dynamic exercise.     

A comparison of the effects of photodynamic therapy on normal and tumor blood vessels in the rat microcirculation

The effects of light activation of the tumor photosensitizer dihematoporphyrin ether (DHE) were studied in the microcirculation of the rat cremaster muscle. Arterioles and venules in an implanted chondrosarcoma were studied by in vivo television microscopy and were compared to normal vessels of the same size elsewhere in the preparation and in control preparations. Activation with green light (530-560 nm, 200 mW/cm2, 120 J/cm2) 48 h after intraperitoneal injection of DHE (10 mg/kg body wt) resulted in significant narrowing of diameters of red blood cell columns in tumor arterioles and venules. The response in normal and control arterioles and venules was not significantly different from that seen in the tumor vessels except that the control arterioles did not remain significantly constricted during the treatment period. Treatment resulted in stasis of blood flow in 90% of tumor and normal arterioles at the completion of light activation. In venules, stasis of blood flow was observed in 75% of tumor and 70% of normal vessels. Vasoconstriction was the primary response in arterioles, while thrombosis predominated in venules. Morphologic assessment of light-activated vessels in the cremaster preparation by transmission electron microscopy revealed platelet aggregation with damage to endothelial cells and smooth muscle cells. Perivascular effects observed included interstitial edema and damage to skeletal muscle cells. In the tumor-bearing preparation, no direct cytotoxic effect on the tumor cells was shown. The surrounding vessels exhibited similar vascular stasis, but the lining cells appeared minimally affected. Photoactivation of DHE results in significant changes in the microcirculation which lead to stasis of blood flow. In this model, the response was similar for the normal microvasculature and for the microcirculation of an implanted chondrosarcoma. These effects may account, in part, for the mechanism of action of photodynamic therapy.     

Patterns of constriction produced by vasoactive agents

The patterns of vasoconstriction produced by local infusions of constrictor agents and neurogenic stimuli are unique and varied. Although vasoconstrictors or neurogenic stimuli may produce similar increases in total resistance to blood flow, the effects on consecutive vascular segments may differ dramatically. Vasoconstrictors may affect primarily small vessels, large vessels, or a combination of both. The constrictor response may be restricted to precapillary vessels or may recruit both pre- and postcapillary vessels. The baroreceptors elicit a pattern of vasoconstriction distinct from that produced by electrical stimulation of a vasomotor nerve. Prearteriolar and venous resistance may contribute more than arterioles to increases in total vascular resistance produced by local infusions of vasoconstrictor agents or nerve stimulation. The constriction of large vessels also affects fluid filtration, vascular capacity, and the distribution of blood flow between shunt and exchange vessels. The waning of the resistance increase that occurs during prolonged infusions of vasoconstrictors varies, in part, as a function of the vessel segments that participate in the vasoconstrictor response. Large vessels participate in vasoconstrictor responses triggered by stimuli that impose a severe stress on the circulation. In contrast, small vessels participate primarily in normal vascular adjustments required to maintain blood pressure at the set point.     

Structural adaptation increases predicted perfusion capacity after vessel obstruction in arteriolar arcade network of pig skeletal muscle

Arteriolar arcades provide alternate pathways for blood flow after obstruction of arteries or arterioles such as occurs in stroke and coronary and peripheral vascular disease. When obstruction is prolonged, remaining vessels adjust their diameters chronically in response to altered hemodynamic and metabolic conditions. Here, the effectiveness of arcades in maintaining perfusion both immediately following obstruction and after structural adaptation was examined. Morphometric data from a vascular casting of the pig triceps brachii muscle and published data were used to develop a computational model for the hemodynamics and structural adaptation of the arcade network between two feed artery branches, FA1 and FA2. The predicted total flow to capillaries (Q(TA)) in the region initially supplied by FA2 decreased to 26% of the normal value immediately after FA2 obstruction but was restored to 78% of the normal value after adaptation. After obstruction of 1-10 randomly selected arcade segments, Q(TA) was on average 18% higher in the arcade network than in a corresponding two-tree network without arcades. Structural adaptation increased Q(TA) by an additional 16% in the arcade network but had almost no effect in the two-tree network. These results indicate that arcades can partially maintain blood flow after vascular blockage and that this effect is substantially enhanced by structural adaptation.     

Network thermodynamic analysis of vasomotion in a microvascular network.

The modulation of microvascular blood flow by vasomotion in the individual vessels of a simple vascular network was simulated by means of a network thermodynamic model. The flow is driven under a pulsating pressure through two arcades of branching vasoactive arterioles into a passive resistance representing the capillary and venular beds. Each vessel was assumed to have the capability of decreasing rhythmically the local diameter over a short section by a specified fraction of the maximum value and to change the average diameter along its total length in response to alterations in intraluminal pressure. Blood was assumed to exhibit a simple linear viscous flow resistance. Alterations in flow rate and distribution through the network were determined as a function of the magnitude and frequency of vasomotion within the individual arterioles supplying blood to the microvascular bed. Specific cases are shown to illustrate how blood flow can be influenced by the patterns of vasomotion within the network.     

Study of tumor blood perfusion and its variation due to vascular normalization by anti-angiogenic therapy based on 3D angiogenic microvasculature

The coupling of intravascular and interstitial flow is a distinct feature of tumor microcirculation, due to high vessel permeability, low osmotic pressure gradient and absence of functional lymphatic system inside tumors. We have previously studied the tumor microcirculation by using a 2D coupled model. In this paper, we extend it to a 3D case with some new considerations, to investigate tumor blood perfusion on a more realist microvasculature, and the effects of vascular normalization by anti-angiogenic therapy on tumor microenvironment.The model predict the abnormal tumor microcirculation and the resultant hostile microenvironment: (1) in the intra-tumoral vessels, blood flows slowly with almost constant pressure values, haematocrit is much lower which contributes to hypoxia and necrosis formation of the tumor centre; (2) the total transvascular flux is at the same order of magnitude as intravascular flux, the intravasation appears inside of the tumor, the ratio of the total amount of intravasation flux to extravasation flux is about 16% for the present model; (3) the interstitial pressure is uniformly high throughout the tumor and drops precipitously at the periphery, which leads to an extremely slow interstitial flow inside the tumor, and a rapidly rising convective flow oozing out from the tumor margin into the surrounding normal tissue. The investigation of the sensitivity of flows to changes in transport properties of vessels and interstitium as well as the vascular density of the vasculature, gains an insight into how normalization of tumor microenvironment by anti-angiogenic therapies influences the blood perfusion.     

Deformation-induced endothelin B receptor-mediated smooth muscle cell apoptosis is matrix-dependent

To maintain normal blood flow, pressure overload in both arteries and veins requires a structural adaptation of the vessel wall (remodelling) that involves smooth muscle cell (SMC) hypertrophy and/or hyperplasia. Due to its potent vasoconstrictor and growth-promoting effects, endothelin-1 (ET-1) is a likely candidate to initiate and/or promote remodelling in blood vessels exposed to a chronic increase in blood pressure. To test this hypothesis, isolated segments of the rabbit carotid artery and jugular vein were perfused at different levels of intraluminal pressure. In both types of segments, pressure overload (160 and 20 mmHg, respectively) resulted in an increase in endothelial prepro-ET-1 and SMC endothelin B receptor (ETB-R) expression. Moreover, in pressurised segments from the carotid artery an ETB-R antagonist-sensitive increase in SMC apoptosis in the media was observed, while in the vein medial SMC started to proliferate. Isolated SMC from these rabbit blood vessels as well as from the aorta and vena cava of the rat, when cultured on a collagen or laminin matrix, uniformly revealed an ETB-R-mediated increase in apoptosis upon exposure to mechanical deformation plus exogenous ET-1 (10 nmol/L). However, when grown on a fibronectin matrix, the cultured SMC did not respond with an increase in apoptosis under otherwise identical experimental conditions. These findings suggest that deformation-induced activation of the endothelin system in the vessel wall not only plays a crucial role in remodelling, but that the structural components of the vessel wall, in particular the cell-matrix interaction, determine how SMC respond phenotypically to these changes in gene expression.     

Viscoelastic properties of microvessels in rat spinotrapezius muscle

In order to establish a quantitative model of blood flow in skeletal muscle, the mechanical properties of the blood vessels need to be measured. We present measurements of the viscoelastic properties of arterioles, venules, and capillaries in exteriorized rat spinotrapezius muscle. Muscles were perfused with an inert silicone polymer and a uniform static pressure was established by occlusion of the venous outflow. Vessel diameters were then measured as a function of the static pressure. This study provides the first measurements of the viscoelastic properties of microvessels in skeletal muscle in situ. Over a pressure range of 20-200 mmHg, the transverse arterioles are the most distensible vessels, while the arcade venules are the stiffest. In response to a step change in pressure, all vessels show an initial elastic deformation, followed by a nonlinear creep. Based on the experimental results for different pressure histories a constitutive equation relating vessel diameter to the local transmural pressure is proposed. Diameter changes are expressed in the form of a diameter strain, analogous to a Green's strain, and are related to the local transmural pressure using a standard linear solid model. This model has only three empirical coefficients and could be fitted to all experimental results for all vessels within error of measurement.     

Photoacoustic microscopy for evaluating a lipopolysaccharide‐induced inflammation model in mice

Photoacoustic microscopy (PAM) is a noninvasive imaging technique and is excellent to study structural and functional changes in the microcirculation. In this work, a lipopolysaccharide (LPS)‐induced inflammation model in mice is noninvasively evaluated by PAM. PAM is used to image the microvascular structural changes in mice for 8 hours after the LPS with different concentrations is applied. Quantitative analysis of five vessel parameters is conducted, which shows that the rate of reduction in microvasculature is highly dependent on the applied LPS concentrations. For low‐concentration LPS, changes in the microvasculature are not obvious over the observation period, whereas for high‐concentration LPS, quick and marked reduction in the microvasculature is observed. In addition, changes in capillaries are more significant than those in relatively large vessels. The results show that PAM is able to evaluate the inflammation mouse model by studying structural (and potentially functional) changes in the microcirculation. Furthermore, PAM may have potential for early intervention and treatment plan optimization of sepsis by monitoring the microcirculation and inflammatory response.      

Arterial supply and venous drainage of the brain of the black bear (Ursus americanus). II. Intracranial microvasculature

A morphological study of the intracranial microvasculature of the Black bear (Ursus americanus) using vascular casts was undertaken. The object was to provide basic information regarding structural modifications of the microvasculature that might provide insight into the ability to cope with low blood flow states that occur during winter sleep. Vascular casts were prepared from 6 animals. The microvasculature of the brain disclosed characteristic features of the small vessels in mammals, including vascular sphincters of two types and numerous arterial and arteriolar anastomoses.     

Dynamic viscous flow in distensible vessels of skeletal muscle microcirculation: application to pressure and flow transients

Blood flow in the microcirculation of the rat skeletal muscle during transient changes of arterial pressure is analyzed theoretically. Although flow in such small vessels is quasi-steady and has a very low Reynolds number, time-dependent nonuniform flows along the length of the blood vessels can be observed due to vessel distensibility. The governing equations for a single microvessel are derived using previously measured microvessel elasticity, and several solutions to different inflow and outflow pressures and flow conditions are investigated. The results indicate that when such distensible microvessels are subjected to a step increase of arterial pressure, the arterial flow shows a rapid overshoot followed by a progressive decay to steady-state. An arterial step flow induces a different response which takes the form of a monotonically increasing pressure. Pressure and flows are nonuniform along the vessel length during such transients. In-vitro whole organ pressure-flow data are presented in the dilated rat gracilis muscle which qualitatively agree with the theoretical predictions.     

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

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

Intravital microscopic observations of 15-microm microspheres lodging in the pulmonary microcirculation.

Vascular infusions of 15-microm-diameter microspheres are used to study pulmonary blood flow distribution. The sites of microsphere lodging and their effects on microvascular perfusion are debated but unknown. Using intravital microscopy of the subpleural surface of rat lungs, we directly observed deposition of fluorescent microspheres. In a pump-perfused lung model, approximately 0.5 million microspheres were infused over 30 s into the pulmonary artery of seven rats. Microsphere lodging was analyzed for the location in the microvasculature and the effect on local flow after lodging. On average, we observed 3.2 microspheres per 160 alveolar facets. The microspheres always entered the arterioles as singlets and lodged at the inlets to capillaries, either in alveolar corner vessels or small arterioles. In all cases, blood flow continued either around the microspheres or into the capillaries via adjacent pathways. We conclude that 15-microm-diameter microspheres, in doses in excess of those used in typical studies, have no significant impact on pulmonary capillary blood flow distribution.     

Effect of the endothelial surface layer on transmission of fluid shear stress to endothelial cells

Responses of vascular endothelial cells to mechanical shear stresses resulting from blood flow are involved in regulation of blood flow, in structural adaptation of vessels, and in vascular disease. Interior surfaces of blood vessels are lined with a layer of bound or adsorbed macromolecules, known as the endothelial surface layer (ESL). In vivo investigations have shown that this layer has a width of order 1 microm, that it substantially impedes plasma flow, and that it excludes flowing red blood cells. Here, the effect of the ESL on transmission of shear stress to endothelial cells is examined using a theoretical model. The layer is assumed to consist of a matrix of molecular chains extending from the surface, held in tension by a slight increase in colloid osmotic pressure relative to that in free-flowing plasma. It is shown that, under physiological conditions, shear stress is transmitted to the endothelial surface almost entirely by the matrix, and fluid shear stresses on endothelial cell membranes are very small. Rapid fluctuations in shear stress are strongly attenuated by the layer. The ESL may therefore play an important role in sensing of shear stress by endothelial cells.     

Structural and hydrodynamic simulation of an acute stenosis-dependent thrombosis model in mice

Platelet activation under blood flow is thought to be critically dependent on the autologous secretion of soluble platelet agonists (chemical activators) such as ADP and thromboxane. However, recent evidence challenging this model suggests that platelet activation can occur independent of soluble agonist signalling, in response to the mechanical effects of micro-scale shear gradients. A key experimental tool utilized to define the effect of shear gradients on platelet aggregation is the murine intravital microscopy model of platelet thrombosis under conditions of acute controlled arteriolar stenosis. This paper presents a computational structural and hydrodynamic simulation of acute stenotic blood flow in the small bowel mesenteric vessels of mice. Using a homogeneous fluid at low Reynolds number (0.45) we investigated the relationship between the local hydrodynamic strain-rates and the severity of arteriolar stensosis. We conclude that the critical rates of blood flow acceleration and deceleration at sites of artificially induced stenosis (vessel side-wall compression or ligation) are a function of tissue elasticity. By implementing a structural simulation of arteriolar side wall compression, we present a mechanistic model that provides accurate simulations of stenosis in vivo and allows for predictions of the effects on local haemodynamics in the murine small bowel mesenteric thrombosis model.     

The State of the Regional Blood Flow in the Upper Extremity after Dosed Physical Exercise

The effect of local isometric exercise on hand and forearm blood flow was studied. With maximum muscular exercise performed by both males and females, a decrease in hand and forearm blood flow was due to vasoconstriction caused by the mechanical pressure of working muscles. With 75 and 50% loads, marked hyperemia was observed in the main and microcirculatory vessels in the hand and forearm, which was rather long-lasting in the hand because of the difficulty of the forearm venous outflow. The minimum loads affected mainly the microcirculation, and no significant hemodynamic changes in main vessels were observed. The exercise performed at 50% of maximum muscular force was taken as an optimum load in kinesotherapeutic programs.     

Control of blood vessel structure: insights from theoretical models

Blood vessels are capable of continuous structural adaptation in response to changing local conditions and functional requirements. Theoretical modeling approaches have stimulated the development of new concepts in this area and have allowed investigation of the complex relations between adaptive responses to multiple stimuli and resulting functional properties of vascular networks. Early analyses based on a minimum-work principle predicted uniform wall shear stress in all segments of vascular networks and led to the concept that vessel diameter is controlled by a feedback system based on responses to wall shear stress. Vascular reactions to changes in transmural pressure suggested feedback control of circumferential wall stress. However, theoretical simulations of network adaptation showed that these two mechanisms cannot, by themselves, lead to stable and realistic network structures. Models combining reactions to fluid shear stress, circumferential stress, and metabolic status of tissue, with propagation of stimuli upstream and downstream along vascular segments, are needed to explain stable and functionally adequate adaptation of vascular structure. Such models provide a basis for predicting the response of vascular segments exposed to altered conditions, as, for example, in vascular grafts.