Regional Blood Flow Research Articles

Numerical Modeling and Simulation of Blood Flow in a Rat Kidney: Coupling of the Myogenic Response and the Vascular Structure

A numerical simulation was carried out to investigate the blood flow behavior (i.e., flow rate and pressure) and coupling of a renal vascular network and the myogenic response to various conditions. A vascular segment and an entire kidney vascular network were modeled by assuming one single vessel as a straight pipe whose diameter was determined by Murray’s law. The myogenic response was tested on individual AA (afferent artery)–GC (glomerular capillaries)–EA (efferent artery) systems, thereby regulating blood flow throughout the vascular network. Blood flow in the vascular structure was calculated by network analysis based on Hagen–Poiseuille’s law to various boundary conditions. Simulation results demonstrated that, in the vascular segment, the inlet pressure Pinlet and the vascular structure act together on the myogenic response of each individual AA–GC–EA subsystem, such that the early-branching subsystems in the vascular network reached the well-regulated state first, with an interval of the inlet as Pinlet = 10.5–21.0 kPa, whereas the one that branched last exhibited a later interval with Pinlet = 13.0–24.0 kPa. In the entire vascular network, in contrast to the Pinlet interval (13.0–20.0 kPa) of the unified well-regulated state for all AA–GC–EA subsystems of the symmetric model, the asymmetric model exhibited the differences among subsystems with Pinlet ranging from 12.0–17.0 to 16.0–20.0 kPa, eventually achieving a well-regulated state of 13.0–18.5 kPa for the entire kidney. Furthermore, when Pinlet continued to rise (e.g., 21.0 kPa) beyond the vasoconstriction range of the myogenic response, high glomerular pressure was also related to vascular structure, where PGC of early-branching subsystems was 9.0 kPa and of late-branching one was 7.5 kPa. These findings demonstrate how the myogenic response regulates renal blood flow in vascular network system that comprises a large number of vessel elements.

This Month in Anesthesiology

This Month in Anesthesiology

Magnetohydrodynamic blood flow study in stenotic coronary artery using lattice Boltzmann method

Background and objective: Cardiovascular diseases such as atherosclerosis are the first engender of death in the world. The malfunctioning of cardiovascular system is attributed mainly to hemodynamics. However, blood magnetic properties are of major haemodynamic interest, with significant clinical applications. The aim of this work is to study numerically the effect of high magnetic field on blood flow in stenotic artery.Methods: In this paper, a double population D2Q9 lattice Boltzmann model is proposed. Velocity and magnetic field are both solved using Lattice Boltzmann method with single relaxation time. Blood is considered homogeneous and Newtonian bio-magnetic fluid. The results of the proposed model are compared and validated by recent numerical and experimental studies in the literature and show good agreement. In this study, simulations are carried out for both hydrodynamics and magneto-hydrodynamics. For the magneto-hydrodynamic case, five values of Hartmann number of 10, 30, 50, 75 and 100 at Reynolds number of 400, 600 and 800 are investigatedResults: The results show that velocity and recirculation zone increase with the increase of the degree of stenosis and Reynolds number. In addition, a considerable decrease in velocity, recirculation zones and pressure drop across the stenotic artery is noticed with the increase of Hartmann number.Conclusion: The suggested model is found to be effective and accurate in the treatment of magneto-hydrodynamic blood flow in stenotic artery. The found results can be used by clinicians in the treatment of certain cardiovascular disorders and in regulating blood flow movement, especially during surgical procedures.

Vascular myogenic control of tibial bone blood flow in young healthy individuals

Bone health is critically dependent on adequate blood flow supplied by its extensive vascular network. Without adequate perfusion to provide oxygen and essential nutrients critical for bone metabolism, nearly all skeletal functions are compromised. However, despite the importance of blood flow to bone, regulation of bone blood flow is poorly understood in humans. The broad hypothesis of the current work is that the primary regulators of blood flow to bone are not different from other vascular beds. We have recently shown that sympathetic innervation of the bone vasculature has an active role in controlling bone blood flow in young healthy individuals. This work furthers our previous findings by investigating additional key bone blood flow regulators ‐ myogenic vasodilation and vasoconstriction. While vascular myogenic control has been investigated in soft tissue, to our knowledge there has been no research in the bone vasculature in humans, with only a handful of animal studies.In young healthy individuals (N=8), we characterized myogenic control of tibial blood flow via novel custom‐made near infrared spectroscopy (NIRS). Tibial blood flow via NIRS was measured as oxy‐, deoxy‐, and total hemoglobin (Hb). We employed reactive hyperemia and leg dependency to assess myogenic vasodilation and vasoconstriction in the whole calf and in the tibia. The magnitude of maximum myogenic vasodilation was defined by the peak reactive blood flow response to sustained ischemia. Arterial flow to the lower leg was occluded by rapidly inflating a pneumatic thigh cuff above the knee to 220 mmHg in supine subjects. Tibial blood flow was assessed via NIRS and whole leg blood flow velocity in the popliteal artery of the same leg was measured via Doppler ultrasound during 1 min of rest, 10 min of cuff inflation, and 5 min of recovery. Myogenic vasoconstriction was assessed via leg dependency, i.e., during two levels of increased transmural pressure achieved by lowering the leg below heart level. Only tibial blood flow was assessed during 5 min in supine position, 5 min in seated upright position, and 5 min in seated position with legs lowered at 90deg knee flexion.During cuff occlusion, there was a time dependent decrease in bone oxyHb accompanied by an increase in deoxyHb indicating lack of flow with continued metabolism. Tibial total Hb (sum of oxy‐ and deoxy‐Hb) did not change significantly during cuff inflation, but increased rapidly and markedly with cuff release, far surpassing baseline values when flow was restored. A similar overshoot response was seen in whole leg blood flow with cuff release. Thus, the response of tibial flow to reactive hyperemia follows the same behavior as the whole limb, indicating an active myogenic vasodilator response in bone similar to other vascular beds. During leg dependency, despite increases in arterial perfusion pressure at both levels (ΔP, 25.8 + 3.67, and 40.0 + 3.02 mmHg), there was no change in tibial flow (total Hb, ‐0.39 + 7.40, and ‐0.29 + 16.2 μM). Hence, unchanged tibial flow despite increased pressure indicates a compensatory vasoconstrictor response in the tibia. Our results indicate that similar to other vascular beds, myogenic control plays an active role in regulating the bone vasculature in young healthy individuals. Characterizing blood flow regulation in bone constitutes the basis of defining its role in overall bone health and its contribution to numerous bone loss conditions.

Rapid Onset Vasodilation: Impact of Cardiorespiratory Fitness

IntroductionHigher cardiorespiratory fitness is associated with greater vascular function that leads to improved regulation of skeletal muscle blood flow during exercise. Rapid onset vasodilation (ROV) describes the immediate increase in blood flow following a single contraction, which is integral to support greater blood flow during exercise. As such, blood flow regulation during exercise hyperemia is important. However, it is unclear if cardiorespiratory fitness plays a role in ROV of small muscle mass in young, healthy individuals.PurposeTo investigate the relationship of cardiorespiratory fitness on ROV following a single handgrip (HG) contraction in young, healthy adults.MethodsCardiorespiratory fitness (VO2peak) was assessed during a maximal cycle ergometer test in 14 volunteers (M/F, 6/8; 28 ± 5yrs; 24.8 ± 4.1kg/m2). Brachial velocity and diameter were measured using duplex Doppler ultrasound for 10 cardiac cycles prior to and 20 cardiac cycles following the first cardiac cycle after a single 30% of maximal voluntary handgrip contraction. Brachial artery blood flow (FBF) was calculated for each cardiac cycle: (diameter2/2)*π*velocity*60. Peak forearm (brachial) blood flow (FBFpeak) was determined as the maximal FBF from baseline following the first cardiac cycle after the single HG contraction. Time to peak blood flow response was determined as the time to reach FBFpeak and heart rate was measured using a three‐lead ECG. The relationship between FBFpeak and time to peak blood flow was tested using a multivariate regression analysis with cardiorespiratory fitness and sex as independent variables.ResultsCardiorespiratory fitness (VO2peak: 30.6 ± 8.0mL/kg/min); β for VO2peak= 0.162 [0.003, 0.327]) was the only predictor of time to peak blood flow response, F(1,12)= 4.602, p= 0.05, R2= 0.217, r= 0.526, while sex (β for time to peak= ‐106.5 [‐156.9, ‐56.2]) was the only predictor of FBFpeak, F(1,12)= 21.245, p<0.001, R2= 0.609, r= 0.799, indicating that females had a lower FBFpeakoverall.ConclusionOur data suggests blood flow responsiveness (e.g., time to peak) is positively associated with cardiorespiratory fitness and these data contribute to our understanding of potential mechanisms between improved blood flow regulation commonly associated with greater cardiorespiratory fitness. More research is necessary to fully elucidate the role biological sex has on these relationships, but our data suggest there may be sex differences in certain blood flow responses.

Mitochondrial oxidative phosphorylation fuels endothelial control of blood vessel tone

Arteries and veins are lined by non‐proliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis to fuel each of these energy‐demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells in angiogenesis, and little is known about energy production in endothelial cells within the fully‐formed vascular wall.Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial oxidative phosphorylation at mitochondrial complex V disrupts calcium‐dependent, nitric oxide‐mediated endothelial cell control of vascular tone. Basal, mechanically‐activated, and agonist‐evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. This effect is mimicked by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for endothelial cell energy production is independent of species, sex, or vascular bed.These data show that mitochondrial ATP is necessary for the obligatory role of endothelial cells in the control of blood vessel diameter, and validate the idea of targeting endothelial cell metabolism to treat endothelial cell dysfunction in cardiovascular disease.

Delayed Reperfusion of the Renal Outer Medulla Attenuates Ischemia Reperfusion‐Induced Vascular Congestion

Vascular congestion, or red blood cell (RBC) trapping, of the renal outer medulla (OM) is a common finding in acute tubular necrosis caused by ischemia reperfusion (IR). Work from our laboratory suggests that vascular congestion originates in the renal venous vasculature of the cortex and OM during the ischemic phase. Following reperfusion, RBCs then fill the OM plexus capillaries as the venous drainage vessels of this region remain blocked. We have also previously reported that pretreatment with low dose lipopolysaccharide (LPS) attenuates IR‐induced vascular congestion, however the mechanisms remain unknown. In the current study, we hypothesized that pretreatment with LPS prevents vascular congestion by delayed reperfusion of blood to the OM following ischemia.To test this hypothesis, WKY rats (male, 12 weeks) were pretreated (i.p) with 1mg/kg LPS (n=6) or saline control (n=7) once daily for 3 days. Rats were then anesthetized, and Transonic Laser Doppler probes were inserted in the renal cortex and OM. Doppler flux, as a determinate of regional kidney blood flow was then measured over 10 minutes of baseline, 45 minutes of renal artery clamping and 30 minutes of reperfusion.We found no differences in baseline blood flow of the cortex (pTREATMENT=0.0543) or OM (pTREATMENT=0.5085) between rats pretreated with low dose LPS or saline control. Following removal of the renal artery clamp, the return of blood flow to the cortex was gradual over the first several minutes of reperfusion (pTIME<0.0001), reaching a plateau following 10 minutes of reperfusion in both treatment groups (pINTERACTION=0.9999) (Fig. A). The reperfusion of blood to the OM, however, rapidly returned to baseline levels within 1 minute of reperfusion in control animals (1 min: 0 to 0.43AU) (Fig. B). In contrast, OM blood flow returned slowly in LPS treated rats (1 min: 0 to ‐0.08AU) and did not return to baseline levels during the 30‐minute reperfusion period (pINTERACTION=0.0127) (Fig. B).These data indicate that LPS pretreatment, paradoxically, delayed early reperfusion of the renal OM via a regional vasoconstriction response. We speculate that delayed reperfusion of the OM attenuates medullary plexus congestion by allowing time for the RBCs in the shared venous circulation to clear. These findings support the hypothesis that reperfusion of the renal outer medullary plexus before cortical perfusion is restored, is responsible for the development of prolonged vascular congestion. New therapeutics focused on renal hemodynamics to prevent congestion after ischemia may prevent much of the injury associated with acute kidney injury.

Examining Vascular Responses to Passive Movement in Premenopausal Females: Comparisons Across Sex and Menstrual Cycle Phase

PurposeVascular responses to passive movement represent a novel assessment of vascular function and serves as a critical component for adequate blood flow regulation during exercise. Although alterations to estradiol (E2) throughout the menstrual cycle, as well as sex differences, are known to impact vascular function, limited research exists in determining whether vascular responses to passive movement are altered in premenopausal females when compared across sex or menstrual cycle phase. We hypothesized that there would be no differences in leg blood flow responses to passive leg movement (PLM) in premenopausal females when compared to age‐matched males or when evaluated across follicular menstrual cycle phases, when E2 fluctuates the most.MethodsVascular responses to one‐minute of PLM were assessed in eleven premenopausal females (n = 21; 23 ± 4 yrs) and age‐matched males (n = 21; 24 ± 4 yrs). All the females completed the PLM assessment during the early (EF) and late follicular (LF) phase of their menstrual cycle, based on self‐reporting of menses. Lower limb microvascular function was assessed during PLM via changes in leg blood flow measured as peak change from baseline (LBFΔPEAK) and area‐under‐the‐curve (LBF AUC). Thigh volume, a known modulator of PLM responses, was also assessed in the passively moved limb in all participants via anthropometric measurements. Blood samples were obtained at rest from the antecubital vein of the arm to determine differences in E2 between the EF and LF phases of the menstrual cycle.ResultsThigh volume differed significantly between the females and age‐matched males (F: 4.9 ± 1.5 L; M: 8.2 ± 1.6 L; p < 0.01) and, when examined in all participants, thigh volume was significantly correlated to PLM‐induced hyperemia evaluated as both LBFΔPEAK (r = 0.6; p < 0.01) and LBF AUC (r = 0.4; p = 0.014). When the group differences in thigh volume were accounted for in the PLM analysis by employing thigh volume as a co‐variate, no significant differences in LBFΔPEAK (F: 542 ± 444; M: 794 ± 444 ml; p = 0.15) and LBF AUC (F: 164 ± 227; M: 249 ± 227 ml; p = 0.3) were revealed. The females reported no significant differences in PLM‐induced blood flow responses across menstrual cycle phases (EF vs LF) evaluated as LBFΔPEAK (EF: 385 ± 186; LF: 386 ± 154 ml; p = 0.9) or LBF AUC (EF: 123 ± 100; LF: 58 ± 84 ml; p = 0.11). Plasma E2 levels were significantly higher in females in the LF phase (215 ± 149 pg/ml) when compared to the EF phase (149 ± 98 pg/ml) of the menstrual cycle (p = 0.01).ConclusionThis study revealed no differences in PLM‐induced LBF responses in premenopausal females when compared to age‐matched males or when assessed across follicular menstrual cycle phases.

Development of thin‐film micro‐outlet devices for spatially constraining local O2 perturbations to capillaries

ObjectiveTo develop and validate thin film micro‐outlet devices to study microvascular blood flow responses to localized changes in skeletal muscle oxygen concentration ([O2]).HypothesisOxygen mediated blood flow regulation is initiated at the capillary level through red blood cell (RBC) oxygen saturation (SO2) dependent mechanisms.Methods10 Sprague‐Dawley rats (159‐190g) were anesthetized and instrumented to maintain cardiovascular state. The right extensor digitorum longus (EDL) muscle was blunt dissected, isolated, and reflected onto a gas exchange chamber (GEC) mounted in the stage of an inverted microscope. The GEC and EDL were coupled via a composite gas permeable membrane and a gas impermeable film fabricated with laser machined micro‐outlets of various diameters (200 μm, 400 μm, 600 μm). [O2] in the EDL was dynamically manipulated by imposing four sequential 1‐ minute [O2] oscillations between 7‐12‐2‐7% while recording intravital video for capillary RBC SO2 and hemodynamic measurement.ResultsO2 oscillations imposed on capillaries directly overlying 400 μm micro‐outlets caused significant changes in capillary SO2 at 12% GEC [O2], 86.72 ± 9.58%, and 2% GEC [O2], 46.36 ± 15.45%, compared to baseline 7% GEC [O2] 69.09 ± 13.94% (p<0.0001). SO2 in capillaries outside the outlet and within a 100 μm distance had significant changes at 2% GEC [O2], 59.38 ± 21.49% compared to baseline 7% GEC [O2], 50.88 ± 18.81% (p<0.0401). SO2 in capillaries >100 μm away from the micro‐outlets were not different following the same GEC [O2] oscillations. GEC [O2] oscillations on capillaries overlying 600 μm micro‐outlets caused significant changes in capillary SO2 at 12% GEC [O2], 83.43 ± 10.18, and 2% GEC [O2], 44.52 ± 15.77%, compared to baseline 7% GEC [O2], 66.27 ± 11.83% (p<0.0001). SO2 in capillaries outside 600 μm outlets were not different following GEC [O2] oscillations. GEC [O2] oscillations on capillaries overlying 400 μm micro‐outlets caused significant changes in capillary RBC supply rate (SR) at 2% GEC [O2], 11.96 ± 9.39 cells/s, compared to baseline 7%, 10.08 ± 7.69 cells/s, and were significantly different at 2% compared to 12% GEC [O2], 9.98 ± 7.99 cells/s (p<0.0014). GEC [O2] oscillations with 600 μm micro‐ outlets caused significant changes in SR at 2% GEC [O2], 14.14 ± 10.52 cells/s compared to baseline 7% GEC [O2], 11.10 ± 9.37 cells/s, as well as a significant change at 2% GEC [O2], compared to 12% GEC [O2], 10.16 ± 8.88 cells/s (p<0.0001).ConclusionsOur composite thin‐film micro‐outlet devices were fabricated and validated to spatially confine O2 perturbations to capillaries using micro‐outlets of varying diameters. These results demonstrate that our devices can profoundly manipulate capillary SO2 and alter capillary RBC SR in vessels directly overlying the micro‐outlet without affecting capillary SO2 at distances greater than 100 μm outside the outlets. 400 μm micro‐outlets are capable of provoking significant changes in capillary SR, with larger 600 μm outlets producing a more robust response. Our novel composite thin‐film micro‐outlet devices demonstrate that regions ~400 μm in diameter must be stimulated to elicit capillary flow responses.

A theoretical model for flow regulation in the cerebral cortex: role of penetrating arterioles

Activation of a region of the brain results in a local increase in blood flow, a process known as neurovascular coupling (NVC). Here, a theoretical model of blood flow regulation in the cerebral cortex is utilized to investigate the potential role of penetrating arterioles as the primary mechanism for local control of blood flow. Penetrating arterioles connect pial arterioles with the capillary meshwork deeper in the cortex and have a typical length of approximately 600 μm. This is about one‐sixth of the length of corresponding small arterioles in skeletal muscle. The question arises whether these relatively short arterioles can achieve the range of flow modulation observed in the cerebral cortex. A previously developed compartmental model for flow regulation in skeletal muscle was modified to represent the structure of cerebral microvasculature. A compartment consisting of penetrating arterioles with a reference diameter of 14.8 μm and a length of 600 μm is assumed to provide active control of blood flow. Smooth muscle tone in these arterioles is assumed to depend on a combination of signals representing myogenic, shear‐dependent, and metabolic responses. The metabolic response is represented by a change in endothelial cell membrane potential, propagated upstream along arterioles by conducted responses. Sensitivity of diameter to membrane potential was determined based on experimental data. According to the model, a hyperpolarization of 40 mV can result in an increase in local blood flow by approximately 70%. Since increases in local blood flow of 50% with activation have been observed, these results imply that vasoconstriction and vasodilation by penetrating arterioles can provide typical levels of blood flow control seen in neurovascular coupling.

Influence of head-up tile and lower body negative pressure on the internal jugular vein.

Head‐up tilt (HUT)‐induced gravitational stress causes collapse of the internal jugular vein (IJV) by decreasing central blood volume and through mass‐effect from the surrounding tissues. Besides HUT, lower body negative pressure (LBNP) is used to stimulate orthostatic stress as an experimental model. Compared to HUT, LBNP has less of a gravitational effect because of the supine position; therefore, we hypothesized that LBNP causes less of a decrease in the cross‐sectional area of the IJV compared to HUT. We tested the hypothesis by measuring the cross‐sectional area of the IJV using B‐mode ultrasonography while inducing orthostatic stress at levels of −40 mmHg LBNP and 60° HUT. The cross‐sectional area of IJV decreased from the resting baseline during both LBNP and HUT trials, but the LBNP‐induced decrease in the cross‐sectional area of IJV was smaller than that of HUT (right, −45% ± 49% vs. −78% ± 27%, p = 0.008; left, −49% ± 27% vs. −78% ± 20%, p = 0.004). Since changes in venous outflow may affect cerebral arterial circulation, the findings of the present study suggest that orthostatic stress induced by different techniques modulates cerebral blood flow regulation through its effect on venous outflow.

Middle‐Aged and Older Adults with Greater White Matter Hyperintensity Burden Display Attenuated Blood Pressure and Cerebral Blood Velocity Responses During Orthostatic Tilt

Cerebral autoregulation (CA) is the process by which the brain maintains adequate blood flow despite sudden changes to perfusion pressure. White matter hyperintensities (WMH) are associated with increased risk of cerebrovascular disease and dementia. This study investigated whether dynamic CA is reduced in cognitively unimpaired middle‐aged and older adults. Additionally, we evaluated dynamic CA and cerebrovascular responses at rest and in response to orthostatic tilt. We hypothesized that CA would be impaired during orthostatic tilt and that diminished blood pressure and cerebral artery blood velocity changes would be associated with greater WMH fraction. We studied 33 middle‐aged and older adults (age = 63 ± 4 y). Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan, respectively, on a 3T MRI scanner. WMH fraction was calculated as the cube root of (WMH lesion volume/ICV) *100. CA was measured using middle cerebral artery blood velocity (MCAv) from transcranial Doppler ultrasound and beat‐to‐beat mean arterial pressure (MAP) from a finger cuff. Five minutes of data were collected at rest and during 60º orthostatic tilt. Transfer function analysis was used to quantify dynamic CA and reported as gain and phase at low frequency (LF) (0.07‐0.20 Hz). MCAv, MAP and cerebrovascular resistance index (CVRi; calculated as MAP/MCAv) were used to quantify the cerebrovascular response to orthostatic tilt. LF gain was greater at baseline compared to 60º tilt (0.52 cm/s/mmHg vs 0.46 cm/s/mmHg, p < 0.05); however, there were no differences in LF phase between baseline and 60º tilt (29.70 degrees vs 29.42 degrees, p = 0.95). During 60º tilt, MAP and MCAv decreased compared to baseline (MAP: 106 mmHg vs 101 mmHg, p = 0.02; MCAv: 59 cm/s vs 53 cm/s, p < .01). CVRi was higher at 60º tilt compared with baseline (1.90 mmHg/cm/s vs 2.02 mmHg/cm/s, p < 0.01). There were significant inverse associations between the percent change from baseline to 60º tilt in MAP (r = ‐0.4, p = 0.03), MCAv (r = ‐0.39, p = 0.03), but not CVRi (r = 0.13, p = 0.50), and WMH fraction. There were no associations at baseline or 60º tilt between gain (Baseline: r = ‐0.18, p = 0.33; 60º: r = ‐0.31, p = 0.09) or phase (Baseline: r = 0.07, p = 0.71; 60º: r = ‐0.29, p = 0.12) and WMH fraction. Our results indicate that dynamic CA is preserved in cognitively unimpaired adults during tilt. However, individuals with diminished MAP and MCAv responses to orthostatic tilt displayed greater WMH fraction. Future studies are needed to investigate the relationship between blood pressure and cerebral blood flow in individuals with cognitive impairment to further understand the role of cerebral blood flow regulation in the development of cognitive decline.

Application of a Second‐Order Control‐Systems Model to Investigate Effects of Impaired Capillary Signalling in Skeletal Muscle on Regulation of Capillary Blood Flow Velocity and Tissue Oxygenation

Microcirculation is the main region of the vasculature where oxygen (O2) is transferred directly from blood to metabolically active tissue. Tissue O2 partial pressure (PO2) in the microcirculation has been historically infeasible to measure, but critical as an indicator of capillary and surrounding tissue health. Thus, theoretical modelling of capillary‐tissue O2 transport is crucial as a complement to in vivo experiments in exploring structure‐function relationships in microvascular networks (Ellis et al, Microcirc 2012, 19:5). To properly complement experiments which stimulate O2 flow‐dependent regulation systems, modelling of microcirculatory O2 transport requires incorporation of knowledge on regulatory mechanisms.Capillary networks modulate their blood velocity to recruit sufficient O2 delivery in many local O2 conditions; this has led to the conclusion that endothelium signals upstream to arterioles in an O2‐dependent manner (Ghonaim et al, Microcirc 2021, e12699). Recently, a second‐order control systems model was developed to investigate the interaction between capillary‐tissue O2 transport and O2‐dependent blood flow regulation under an externally applied O2 stimulus. This utilized elements from previous arteriolar diameter alteration models in response to skeletal muscle O2 gradients, as well as elements from a recently developed continuous‐capillary O2 transport model (Afas et al, Math Biosci 2021, 333:108535).The control systems model aimed to predict modulations in blood velocity through endothelial signalling which homogenized outlet capillary PO2 in skeletal muscle. The model demonstrated that variations in O2 transport parameters such as capillary network density and tissue O2 consumption rate had varying effects on the averaged blood velocity in a small skeletal muscle segment perfused by a capillary network. In addition, the externally supplied PO2 had an effect on both blood velocity and the tissue‐capillary O2 balance. While the tissue‐capillary PO2 balance and velocity adaptation were investigated, the endothelial signalling parameters were not reported (Afas & Goldman, Vasc. Bio. 2021, conference).The present study investigates implications of capillary network metric variations on the endothelial signal communicated upstream to modulate capillary blood flow in response to various muscle surface PO2 levels. Constraints imposed by pathogenic impairment of endothelial signalling will be investigated and interpreted in the context of capillary flow regulation.

Conducted Capillary Signaling Enables Oxygen Responses in Skeletal Muscle Independent of Metabolite Production

Red blood cell (RBC) flow through the microvasculature is closely matched to tissue O2 requirements. At a fundamental level, O2 demand‐supply coupling entails the sensing of PO2, and the generation of a stimulus that alters upstream arteriolar tone. However, where and how O2 needs are sensed in the microcirculation is presently contested. One idea centers on hypoxia triggering the release of K+, activating endothelial KIR2.1 channels and initiating a hyperpolarization that conducts upstream via gap junctions, comprised of connexins (Cx). We tested this idea in skeletal muscle where we controlled the local tissue O2 environment using live animal imaging in Cx40‐/‐and endothelial KIR2.1‐/‐ mice. The extensor digitorum longus muscle positioned overtop a gas control chamber allowed second‐by‐second monitoring of capillary RBC flow responses as O2 was altered around its physiological set point of 53 mmHg. A stepwise drop in PO2 at the muscle surface (53 to 15 or 0 mmHg) increased RBC supply rate in control capillaries while elevated chamber O2 elicited the opposite response; these capillaries robustly expressed Cx40. The RBC flow responses were rapid and tightly coupled to O2 levels as readily observed when chamber O2 was oscillated in a sinusoidal manner. In contrast, this blood flow response was significantly diminished in Cx40‐/‐ mice and translated into lower capillary RBC O2 saturation. KIR2.1‐/‐mice, on the other hand, had normal resting RBC O2 saturation and reacted normally to O2 changes, albeit an oscillation or a sustained stepwise decrease. Furthermore, we confirmed that RBC flow responses are conserved in endothelial KIR2.1‐/‐mice even when the low O2 challenge is applied to a restricted number of surface capillaries in the muscle; interestingly, these responses were dominated by capillary hematocrit changes in both control and endothelial KIR2.1‐/‐mice. Modelling this phenomenon supported the idea that the number of capillaries stimulated is indeed tied to conduction distance and tissue RBC distribution. In conclusion, we demonstrate that microvascular O2 responses depend on coordinated electrical signaling via gap junctions comprised of Cx40 and that endothelial KIR2.1channels do not drive the initiating electrical event. These findings reconceptualize our understanding of blood flow regulation and how O2 initiates this process at the capillary level independent of metabolite production.

ATP Attenuates α1‐Adrenergic and Peptidergic Vasocontraction in Isolated Porcine Cerebral Arteries

IntroductionCompeting influences regulate blood flow control in the brain. In the skeletal muscle vasculature, purinergic ATP signaling attenuates α1‐adrenergic and peptidergic‐induced vascular smooth muscle contraction (i.e., phenomenon referred to as functional sympatholysis); however, whether this occurs in the cerebrovasculature remains unknown. The purpose of this experiment was to examine the effect of ATP on vascular responses to α1‐adrenergic‐ and peptidergic‐receptor activation in cerebral arteries. We hypothesized that ATP would attenuate the α1‐adrenergic‐ and peptidergic‐mediated vasocontraction in isolated pial arteries.MethodsFemale pigs (n=5) were euthanized and their brains harvested. Thereafter, 1A branches of the middle cerebral artery were dissected for wire‐myography. Dose‐response curves for the α1‐adrenergic agonist phenylephrine (PE;1e‐10‐1e‐4M) and the peptidergic agonist neuropeptide Y (NPY;1e‐12‐1e‐6M) were performed in the absence or presence of ATP (1e‐6M). Paired one‐tailed t‐tests were used to compare the overall magnitude of contraction (area under the curve; AUC) and physiological maximal responses between conditions.ResultsData are mean±SD. The AUC of PE‐mediated cerebral vasocontraction was attenuated by ATP (untreated=67±25 vs. ATP pre‐treatment=33±23 AU; p=0.03). However, the mean reduction in the maximal response to PE in arteries pre‐treated with ATP was not significant (untreated=43±15 vs. ATP pre‐treatment=27±11%; p=0.10). The AUC (untreated=62±31 vs. ATP pre‐treatment=37±23 AU) as well as maximal NPY‐mediated cerebral vasocontraction (untreated=65±20 vs. ATP pre‐treatment=49±21%) was attenuated by ATP (all p≤0.05).ConclusionThese data indicate ATP attenuates PE‐ and NPY‐mediated vasocontraction in isolated pial arteries. Thus, similar to the skeletal muscle vasculature, purinergic signaling attenuates vasoreactivity to α1‐adrenergic and peptidergic receptor activation in the cerebrovasculature. Functional sympatholysis may assist in coupling cerebral blood flow to brain metabolism under basal conditions as well as in the setting of heightened sympatho‐excitation.

The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Lung perfusion during veno-venous extracorporeal membrane oxygenation in a model of hypoxemic respiratory failure

BackgroundVeno-venous extracorporeal membrane oxygenation (ECMO) provides blood oxygenation and carbon dioxide removal in acute respiratory distress syndrome. However, during ECMO support, the native lungs still play an important role in gas exchange, functioning as a second oxygenator in series with ECMO. The hypoxic vasoconstriction mechanism diverts regional blood flow within the lungs away from regions with low oxygen levels, optimizing ventilation/perfusion matching. ECMO support has the potential to reduce this adaptive pulmonary response and worsen the ventilation/perfusion mismatch by raising venous oxygen partial pressure. Thus, the objective of this study was to evaluate the effect of ECMO on regional pulmonary perfusion and pulmonary hemodynamics during unilateral ventilation and posterior lung collapse.MethodsFive Agroceres pigs were instrumented, monitored and submitted to ECMO. We used the Electrical Impedance Tomography (EIT) to evaluate lung ventilation and perfusion in all protocol steps. Effects of ECMO support on pulmonary hemodynamics and perfusion involving two different scenarios of ventilation/perfusion mismatch: (1) right-lung selective intubation inducing collapse of the normal left lung and (2) dorsal lung collapse after repeated lung lavage. Data including hemodynamics, respiratory, lung perfusion/ventilation, and laboratory data over time were analyzed with a mixed generalized model using the subjects as a random factor.ResultsThe initiation of ECMO support provided a significant reduction in Mean Pulmonary Artery Pressure (PAPm) in both situations of ventilation/perfusion mismatch. However, distribution of lung perfusion did not change with the use of ECMO support.ConclusionsWe found that the use of ECMO support with consequent increase in venous oxygen pressure induced a significant drop in PAPm with no detectable effect on regional lung perfusion in different scenarios of ventilation/perfusion mismatch.

The impact of obesity on the regulation of muscle blood flow during exercise in patients with heart failure with a preserved ejection fraction.

Obesity is now considered a primary comorbidity in heart failure with preserved ejection fraction (HFpEF) pathophysiology, mediated largely by systemic inflammation. Although there is accumulating evidence for a disease-related dysregulation of blood flow during exercise in this patient group, the role of obesity in the hemodynamic response to exercise remains largely unknown. Small muscle mass handgrip (HG) exercise was used to evaluate exercising muscle blood flow in nonobese (BMI < 30 kg/m2, n = 14) and obese (BMI > 30 kg/m2, n = 40) patients with HFpEF. Heart rate (HR), stroke index (SI), cardiac index (CI), mean arterial pressure (MAP), forearm blood flow (FBF), and vascular conductance (FVC) were assessed during progressive intermittent HG exercise [15%-30%-45% maximal voluntary contraction (MVC)]. Blood biomarkers of inflammation [C-reactive protein (CRP) and interleukin-6 (IL-6)] were also determined. Exercising FBF was reduced in obese patients with HFpEF at all work rates (15%: 304 ± 42 vs. 229 ± 15 mL/min; 30%: 402 ± 46 vs. 300 ± 18 mL/min; 45%: 484 ± 55 vs. 380 ± 23 mL/min, nonobese vs. obese, P = 0.025), and was negatively correlated with BMI (R = -0.47, P < 0.01). In contrast, no differences in central hemodynamics (HR, SI, CI, and MAP) were found between groups. Proinflammatory biomarkers were markedly elevated in patients with obesity (CRP: 2,133 ± 418 vs. 4,630 ± 590 ng/mL, P = 0.02; IL-6: 2.9 ± 0.3 vs. 5.2 ± 0.7 pg/mL, nonobese vs. obese, P = 0.04), and both biomarkers were positively correlated with BMI (CRP: R = 0.40, P = 0.03; IL-6: R = 0.57, P < 0.01). Together, these findings demonstrate the presence of obesity and an accompanying milieu of systemic inflammation as important factors in the dysregulation of exercising muscle blood flow in patients with HFpEF.NEW & NOTEWORTHY Obesity is the primary comorbid condition in HFpEF pathophysiology, but the role of adiposity on the peripheral circulation is not well understood. The present study identified a 30%-40% reduction in forearm blood flow during handgrip exercise, accompanied by a marked elevation in proinflammatory plasma biomarkers, in obese patients with HFpEF compared with their nonobese counterparts. These findings suggest an exaggerated dysregulation in exercising muscle blood flow associated with the obese HFpEF phenotype.

The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets.

Ischemic stroke (IS) is a cerebrovascular disease causing high rates of disability and fatality. In recent years, the concept of the neurovascular unit (NVU) has been accepted by an increasing number of researchers and is expected to become a new paradigm for exploring the pathogenesis and treatment of IS. NVUs are composed of neurons, endothelial cells, pericytes, astrocytes, microglia, and the extracellular matrix. As an important part of the NVU, pericytes provide support for other cellular components and perform a variety of functions, including participating in the maintenance of the normal physiological function of the blood–brain barrier, regulating blood flow, and playing a role in inflammation, angiogenesis, and neurogenesis. Therefore, treatment strategies targeting pericyte functions, regulating pericyte epigenetics, and transplanting pericytes warrant exploration. In this review, we describe the reactions of pericytes after IS, summarize the potential therapeutic targets and strategies targeting pericytes for IS, and provide new treatment ideas for ischemic stroke.

Highlights From the Circulation Family of Journals

Highlights From the <i>Circulation</i> Family of Journals