Microvascular Pressure Research Articles

Hydrostatic pressure drives sprouting angiogenesis via adherens junction remodelling and YAP signalling

Endothelial cell physiology is governed by its unique microenvironment at the interface between blood and tissue. A major contributor to the endothelial biophysical environment is blood hydrostatic pressure, which in mechanical terms applies isotropic compressive stress on the cells. While other mechanical factors, such as shear stress and circumferential stretch, have been extensively studied, little is known about the role of hydrostatic pressure in the regulation of endothelial cell behavior. Here we show that hydrostatic pressure triggers partial and transient endothelial-to-mesenchymal transition in endothelial monolayers of different vascular beds. Values mimicking microvascular pressure environments promote proliferative and migratory behavior and impair barrier properties that are characteristic of a mesenchymal transition, resulting in increased sprouting angiogenesis in 3D organotypic model systems ex vivo and in vitro. Mechanistically, this response is linked to differential cadherin expression at the adherens junctions, and to an increased YAP expression, nuclear localization, and transcriptional activity. Inhibition of YAP transcriptional activity prevents pressure-induced sprouting angiogenesis. Together, this work establishes hydrostatic pressure as a key modulator of endothelial homeostasis and as a crucial component of the endothelial mechanical niche.

High Blood Pressure, Hyperlipidemia, Type2 Diabetes with Prior History of Arterial Fibrilation Caused Stroke

The stroke cases are on rise, to know its causes, symptoms & treatment patients have to be studied in detail and get the appropriate result. Stroke is a serious medical condition that can sometimes be deadly. Stroke cases are emerging at a startling rate at the moment. People with specific medical problems are more susceptible to stroke, even though it may afflict anybody. A stroke or brain stroke can be fatal and result from inadequate blood supply to a portion of the brain, according to the Cleveland Clinic. The most common causes of this are cerebral haemorrhage or arterial obstruction. If insufficient blood flow occurs, oxygen-starved brain cells begin to die. A stroke may happen to anybody, at any age, although certain people are more susceptible than others. Furthermore, beyond the age of 65, the danger rises. Strokes occur commonly in either sex. Strokes are the second largest cause of mortality worldwide. Not only that, but stroke is a leading global cause of disability. The following are a few examples of stroke symptoms Paralysis on one sides peaking difficulties or loss of speech distorted or double vision (diplopia) inability to coordinate light headedness and vomiting stiff neck personality shift agitation or confusion seizure loss of memory headache loss of consciousness the blood clotting disorder atherosclerosis Heart abnormality (ventricular or atrial septal defect) microvascular ischemia elevated blood pressure tumours of the brain (including cancer)Heart abnormality (ventricular or atrial septal defect) microvascular ischemia elevated blood pressure tumours of the brain (including cancer) etc.

Negative pressure pulmonary edema (Review).

Negative pressure pulmonary edema (NPPE) is a complication resulting from acute or chronic upper airway obstruction, often posing challenges in recognition and diagnosis for clinicians. If left untreated, NPPE can lead to hypoxemia, heart failure and even shock. Furthermore, the drug treatment of NPPE remains a subject of controversy. The primary pathophysiological mechanism of NPPE involves the need for high inspiratory pressure to counteract upper airway obstruction, subsequently causing a progressive rise in negative pressure within the pleural cavity. Consequently, this results in increased pulmonary microvascular pressure, leading to the infiltration of pulmonary capillary fluid into the alveoli. NPPE exhibits numerous risk factors and causes, with laryngospasm following anesthesia and extubation being the most prevalent. The diagnosis of NPPE often presents challenges due to confusion with conditions such as gastroesophageal reflux or cardiogenic pulmonary edema, given the similarity in initial factors triggering both diseases. Upper airway patency, positive pressure non-invasive ventilation, supplemental oxygen and re-intubation mechanical ventilation are the foundation of the treatment of NPPE. The present review aims to discuss the etiology, clinical presentation, pathophysiology and management of NPPE.

Furosemide exacerbated the impairment of renal function, oxygenation and medullary damage in a rat model of renal ischemia/reperfusion induced AKI

BackgroundPerioperative acute kidney injury (AKI) caused by ischemia–reperfusion (IR) is a significant contributor to mortality and morbidity after major surgery. Furosemide is commonly used in postoperative patients to promote diuresis and reduce tissue edema. However, the effects of furosemide on renal microcirculation, oxygenation and function are poorly understood during perioperative period following ischemic insult. Herein, we investigated the effects of furosemide in rats subjected IR insult.Methods24 Wistar albino rats were divided into 4 groups, with 6 in each; Sham-operated Control (C), Control + Furosemide (C + F), ischemia/reperfusion (IR), and IR + F. After induction of anesthesia (BL), supra-aortic occlusion was applied to IR and IR + F groups for 45 min followed by ongoing reperfusion for 15 min (T1) and 2 h (T2). Furosemide infusion was initiated simultaneously in the intervention groups after ischemia. Renal blood flow (RBF), vascular resistance (RVR), oxygen delivery (DO2ren) and consumption (VO2ren), sodium reabsorption (TNa+), oxygen utilization efficiency (VO2/TNa+), cortical (CμO2) and medullary (MμO2) microvascular oxygen pressures, urine output (UO) and creatinine clearance (Ccr) were measured. Biomarkers of inflammation, oxidative and nitrosative stress were measured and kidneys were harvested for histological analysis.ResultsIR significantly decreased RBF, mainly by increasing RVR, which was exacerbated in the IR + F group at T2 (2198 ± 879 vs 4233 ± 2636 dyne/s/cm5, p = 0.07). CμO2 (61.6 ± 6.8 vs 86 ± 6.6 mmHg) and MμO2 (51.1 ± 4.1 vs 68.7 ± 4.9 mmHg, p < 0.05) were both reduced after IR and did not improve by furosemide. Moreover, VO2/TNa+ increased in the IR + F group at T2 with respect to the IR group (IR: 3.3 ± 2 vs IR + F: 8.2 ± 10 p = 0.07) suggesting a possible deterioration of oxygen utilization. Ccr did not change, but plasma creatinine increased significantly in IR + F groups. Histopathology revealed widespread damage both in the cortex and medulla in IR, IR + F and C + F groups.ConclusionRenal microvascular oxygenation, renal function, renal vascular resistance, oxygen utilization and damage were not improved by furosemide administration after IR insult. Our study suggests that furosemide may cause additional structural and functional impairment to the kidney following ischemic injury and should be used with caution.

Measurements of cerebral microvascular blood flow, oxygenation, and morphology in a mouse model of whole-brain irradiation-induced cognitive impairment by two-photon microscopy and optical coherence tomography: evidence for microvascular injury in the cerebral white matter.

Whole-brain irradiation (WBI, also known as whole-brain radiation therapy) is a mainstay treatment modality for patients with multiple brain metastases. It is also used as a prophylactic treatment for microscopic tumors that cannot be detected by magnetic resonance imaging. WBI induces a progressive cognitive decline in ~ 50% of the patients surviving over 6months, significantly compromising the quality of life. There is increasing preclinical evidence that radiation-induced injury to the cerebral microvasculature and accelerated neurovascular senescence plays a central role in this side effect of WBI. To better understand this side effect, male C57BL/6 mice were first subjected to a clinically relevant protocol of fractionated WBI (5Gy, two doses per week, for 4weeks). Nine months post the WBI treatment, we applied two-photon microscopy and Doppler optical coherence tomography to measure capillary red-blood-cell (RBC) flux, capillary morphology, and microvascular oxygen partial pressure (PO2) in the cerebral somatosensory cortex in the awake, head-restrained, WPI-treated mice and their age-matched controls, through a cover-glass-sealed chronic cranial window. Thanks to the extended penetration depth with the fluorophore - Alexa680, measurements of capillary blood flow properties (e.g., RBC flux, speed, and linear density) in the cerebral subcortical white matter were enabled. We found that the WBI-treated mice exhibited a significantly decreased capillary RBC flux in the white matter. WBI also caused a significant reduction in capillary diameter, as well as a large (although insignificant) reduction in segment density at the deeper cortical layers (e.g., 600-700μm), while the other morphological properties (e.g., segment length and tortuosity) were not obviously affected. In addition, we found that PO2 measured in the arterioles and venules, as well as the calculated oxygen saturation and oxygen extraction fraction, were not obviously affected by WBI. Lastly, WBI was associated with a significant increase in the erythrocyte-associated transients of PO2, while the changes of other cerebral capillary PO2 properties (e.g., capillary mean-PO2, RBC-PO2, and InterRBC-PO2) were not significant. Collectively, our findings support the notion that WBI results in persistent cerebral white matter microvascular impairment, which likely contributes to the WBI-induced brain injury and cognitive decline. Further studies are warranted to assess the WBI-induced changes in brain tissue oxygenation and malfunction of the white matter microvasculature as well.

Magnetic Resonance Imaging-Derived Microvascular Perfusion Modeling to Assess Peripheral Artery Disease.

Background Computational fluid dynamics has shown good agreement with contrast-enhanced magnetic resonance imaging measurements in cardiovascular disease applications. We have developed a biomechanical model of microvascular perfusion using contrast-enhanced magnetic resonance imaging signal intensities derived from skeletal calf muscles to study peripheral artery disease (PAD). Methods and Results The computational microvascular model was used to study skeletal calf muscle perfusion in 56 individuals (36 patients with PAD, 20 matched controls). The recruited participants underwent contrast-enhanced magnetic resonance imaging and ankle-brachial index testing at rest and after 6-minute treadmill walking. We have determined associations of microvascular model parameters including the transfer rate constant, a measure of vascular leakiness; the interstitial permeability to fluid flow which reflects the permeability of the microvasculature; porosity, a measure of the fraction of the extracellular space; the outflow filtration coefficient; and the microvascular pressure with known markers of patients with PAD. Transfer rate constant, interstitial permeability to fluid flow, and microvascular pressure were higher, whereas porosity and outflow filtration coefficient were lower in patients with PAD than those in matched controls (all P values ≤0.014). In pooled analyses of all participants, the model parameters (transfer rate constant, interstitial permeability to fluid flow, porosity, outflow filtration coefficient, microvascular pressure) were significantly associated with the resting and exercise ankle-brachial indexes, claudication onset time, and peak walking time (all P values ≤0.013). Among patients with PAD, interstitial permeability to fluid flow, and microvascular pressure were higher, while porosity and outflow filtration coefficient were lower in treadmill noncompleters compared with treadmill completers (all P values ≤0.001). Conclusions Computational microvascular model parameters differed significantly between patients with PAD and matched controls. Thus, computational microvascular modeling could be of interest in studying lower extremity ischemia.

Factors Regulating Fluid Restitution and Plasma Volume Reduction over the Course of Hemodialysis.

Over the course of hemodialysis, fluid and protein are restituted from the tissue compartment to the circulation compartment through the endothelia. Our previous model analysis on fluid and protein transport during hemodialysis is expanded to account for changes occurring in the tissue. The measured initial and end plasma protein concentration (PPC, Cp and Cp') for six hemodialysis studies are analyzed by this expanded model. The computation results indicate that the total driving pressure to restitute fluid from the tissue to the circulation ranges from 5.4 to 20.3 mmHg. The analysis identifies that the increase in plasma colloidal osmotic pressure (COP) contributes 78 ± 6% of the total driving pressure, the decrease in microvascular blood pressure 32 ± 4%, the increase in the COP of interstitial fluid -6 ± 3%, and the decrease in interstitial fluid pressure -5 ± 2%. Let this ratio (Cp' - Cp)/Cp' be termed the PPC increment. The six HDs can be divided into three groups which are to have these PPC increments 25.7%, 14.5 ± 2.6(SD)% and 8.3%. It is calculated that their correspondent filtration coefficients are 0.43, 1.29 ± 0.28 and 5.93 mL/min/mmHg and the relative reductions in plasma volume (RRPV) -22.1%, -13.1 ± 6% and -9.4%. The large variations in PPC increments and RRPV show the filtration coefficient is a key factor to regulate the hemodialysis process.

No effect of nitrate-rich beetroot juice on microvascular function and blood pressure in younger and older individuals: a randomised, placebo-controlled double-blind pilot study

Background/ObjectivesTo compare the effects of supplemental inorganic nitrate (NO3) on microvascular endothelial function and blood pressure in younger vs. older participants.Subjects/Methods25 individuals participated in a double-blind, randomised, placebo-controlled crossover pilot study. Participants were stratified by age (18–35 and ≥55 years) and consumed a single dose beetroot juice (providing 6.4 mmol NO3) or NO3-depleted beetroot juice. Blood pressure, microvascular function (via Laser Doppler Flowmetry; LDF) and urinary NO3 were assessed, and the effects of NO3 supplementation on cardiovascular parameters were compared between participants and conditions using mixed-design ANOVA.ResultsTreatments and methods were well tolerated, and no adverse events were reported. Urinary NO3 increased 3 h following ingestion in both groups, (P = 0.02). Levels remained elevated at 24 h post consumption in younger participants only (P = 0.02). Beetroot juice had no effect on blood pressure in either group nor on microcirculatory endothelial function.ConclusionsBeetroot juice had no effect on blood pressure or microvascular endothelial function in young and older individuals. Dosage and timing regimens for supplemental beetroot juice should be avenues for further inquiry.

Myocardial Edema Provides a Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.

Myocardial Edema Provides a Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.

A systematic review of the prevalence, risk factors and screening tools for autonomic and diabetic peripheral neuropathy in children, adolescents and young adults with type 1 diabetes.

We aimed to estimate the prevalence of Diabetic peripheral neuropathy (DPN) and Cardiac autonomic neuropathy (CAN) in youth with type 1 diabetes; identify key risk factors; identify the most useful tests for the diagnostic evaluation of DPN and CAN; identify key treatment options for DPN and CAN. A systematic search was performed including studies published in the last 15years. PICO framework was used in the selection process and evidence was assessed using the GRADE system. A total of 758 studies were identified and a final number of 49 studies were included in this systematic review. According to moderate-high level quality studies, the prevalence of probable DPN, ranged between 13.5 and 62%; subclinical DPN between 22 and 88%; confirmed DPN between 2.6 and 11%. The Michigan Neuropathy Screening Instrument was the tool with higher sensitivity and specificity for detecting DPN, which needs to be confirmed by nerve conduction velocity. The prevalence of CAN was 4-39%. Specific treatment options for DPN or CAN in patients younger than 25years are not available. Key risk factors for DPN and CAN are hyperglycemia/HbA1c, age, diabetes duration, the presence of other microvascular complications, waist/height ratio, lipid profile and blood pressure. For CAN, additional risk factors were cigarette smoking, BMI and total daily insulin. Prevalence of neuropathy in youth with type 1 diabetes varies depending on different screening methods and characteristics of the study populations. However, the assessed studies confirmed a relatively high prevalence of subclinical neuropathy, reiterating the importance of early identification of risk factors to prevent this complication.

Increased Hepatic Microvascular Density, Oxygenation, and VEGF in the Hypertrophic Lobe following Portal Vein Embolization in Rabbits

Introduction: The microvascular events following portal vein embolization (PVE) are poorly understood despite the pivotal role of the microcirculation in liver regeneration and tumor progression. We aimed to assess the changes in hepatic microvascular perfusion and neo-angiogenesis after experimental PVE. Methods: PVE of the cranial liver lobes was performed in 12 New Zealand White rabbits divided into 2 groups of permanent (P-PVE) and reversible PVE (R-PVE), respectively. Hepatobiliary scintigraphy and CT were used to evaluate hepatic function and volume. Hepatic microcirculation was assessed using a handheld vital microscope (Cytocam) to measure microvascular density (total vessel density; TVD) before PVE, right after PVE, and 20 min after PVE, as well as at 14 days (D14 post-PVE) and 35 days (D35 post-PVE). Additionally, on D35, microvascular PO₂ and liver parenchymal VEGF were assessed. Results: Eleven rabbits were included after PVE (R-PVE, n = 5; P-PVE, n = 6). TVD in the nonembo­lized (hypertrophic) lobes was higher than in the embolized (atrophic) lobes of the P-PVE group at D35 post-PVE (36.7 ± 7.2 vs. 23.4 ± 4.9 mm/mm²; p < 0.05). In the R-PVE group, TVD in the nonembolized lobes was not increased at D35. Function and volume were increased in the nonembolized lobes of the P-PVE group compared to the embolized lobes, but not in the R-PVE group. Likewise, the mmicrovascular PO₂ and VEGF staining rate were higher in the nonembolized lobes of the P-PVE group at D35 post-PVE. Discussion/Conclusion: Successful volumetric and functional hypertrophy of the nonembolized lobe was accompanied by microvascular alterations featuring increased neo-angiogenesis, microvascular density, and microvascular oxygen pressure following P-PVE.

A poroelasticity model for interstitial fluid flow and matrix deformation in a non-homogeneous solid tumor

This paper describes a small-strain poroelasticity model to examine the interstitial fluid pressure and matrix deformation in a non-homogeneous solid tumor consisting of an inner core with a reduced specific microvascular area encapsulated in an outer tissue shell with a regular specific microvascular area. A singular perturbation technique is employed to capture the transitional behavior at the interface between the inner core and outer shell under a cyclic microvascular pressure. The perturbation solution reveals the existence of two boundary layers: one at the interface between the inner core and outer shell, and the other at the tumor surface. The amplitude of the tumor interstitial fluid (TIF) pressure is at a lower constant level in the inner core and increases rapidly in the boundary layer at the interface between the inner core and outer shell to the pressure value of the corresponding homogeneous tumor with the outer shell properties. The radial strain undergoes dramatic changes in the boundary layers, and reaches the peak near the interface between the inner core and outer shell. The behavior of the effective stresses remains similar to that of the TIF pressure.

Renal microvascular oxygen tension during hyperoxia and acute hemodilution assessed by phosphorescence quenching and excitation with blue and red light.

The kidney plays a central physiologic role as an oxygen sensor. Nevertheless, the direct mechanism by which this occurs is incompletely understood. We measured renal microvascular partial pressure of oxygen (PkO2) to determine the impact of clinically relevant conditions that acutely change PkO2 including hyperoxia and hemodilution. We utilized two-wavelength excitation (red and blue spectrum) of the intravascular phosphorescent oxygen sensitive probe Oxyphor PdG4 to measure renal tissue PO2 in anesthetized rats (2% isoflurane, n = 6) under two conditions of altered arterial blood oxygen content (CaO2): 1) hyperoxia (fractional inspired oxygen 21%, 30%, and 50%) and 2) acute hemodilutional anemia (baseline, 25% and 50% acute hemodilution). The mean arterial blood pressure (MAP), rectal temperature, arterial blood gases (ABGs), and chemistry (radiometer) were measured under each condition. Blue and red light enabled measurement of PkO2 in the superficial renal cortex and deeper cortical and medullary tissue, respectively. PkO2 was higher in the superficial renal cortex (~ 60 mmHg, blue light) relative to the deeper renal cortex and outer medulla (~ 45 mmHg, red light). Hyperoxia resulted in a proportional increase in PkO2 values while hemodilution decreased microvascular PkO2 in a linear manner in both superficial and deeper regions of the kidney. In both cases (blue and red light), PkO2 correlated with CaO2 but not with MAP. The observed linear relationship between CaO2 and PkO2 shows the biological function of the kidney as a quantitative sensor of anemic hypoxia and hyperoxia. A better understanding of the impact of changes in PkO2 may inform clinical practices to improve renal oxygen delivery and prevent acute kidney injury.

Abnormalities of the lymphatic system and impaired fluid clearance in patients with heart failure with preserved ejection fraction

Abstract Background Coronary and skeletal muscle microvascular dysfunction have been proposed as main factors in the pathogenesis of Heart Failure with Preserved Ejection Fraction (HFpEF). However, assessment of systemic arterial function has only been indirect thus far; most importantly, no direct link between systemic microvasculature and congestion, one of the core characteristics of the syndrome, has yet been investigated. Purpose To provide direct functional and anatomical characterisation of the systemic microvasculature and to explore in vivo parameters of capillary fluid extravasation and lymphatic clearance in HFpEF. Methods In 16 patients with HFpEF and 16 age- and sex-matched healthy controls (72±6 and 68±5 years, respectively) we determined peripheral microvascular filtration coefficient (proportional to vascular permeability and area) and isovolumetric pressure (above which lymphatic drainage cannot compensate for fluid extravasation) by venous occlusion plethysmography and collected a skin biopsy for vascular immunohistochemistry and gene expression analysis (TaqMan). Additionally, we measured brachial flow-mediated dilatation (FMD) and assessed by wire myography the vascular function of resistance arteries isolated from gluteal subcutaneous fat biopsies. Results Skin biopsies in patients with HFpEF showed rarefaction of small blood vessels (82±31 vs 112±21 vessels/mm2; p=0.003) and in ex-vivo analysis (n=6/group) we found defective relaxation of peripheral resistance arteries (p&amp;lt;0.001). Accordingly, post-ischaemic hyperaemic response (fold-change vs baseline, 4.6±1.6 vs 6.7±1.7; p=0.002) and FMD (3.9±2.1 vs 5.6±1.5%; p=0.014) were found to be reduced in patients with HFpEF compared to controls. In the skin of patients with HFpEF we also observed a reduced number (85±27 vs 130±60 vessels/mm2; p=0.012) but larger average diameter of lymphatic vessels (42±19 vs 26±9 μm2; p=0.007) compared to control subjects. These changes were paralleled by reduced expression of LYVE1 (p&amp;lt;0.05) and PROX1 (p&amp;lt;0.001), key determinants of lymphatic differentiation and function. Whilst patients with HFpEF had reduced peripheral capillary fluid extravasation compared to controls (microvascular filtration coefficient, leg 33.1±13.3 vs 48.4±15.2, p&amp;lt;0.01; trend for arm 49.9±20.5 vs 66.3±30.1, p=0.09), they had lower lymphatic clearance (isovolumetric pressure: leg 22±4 vs 16±4 mmHg, p&amp;lt;0.005; arm 25±5 vs 17±4 mmHg, p&amp;lt;0.001). Conclusions We provide direct evidence of systemic dysfunction and rarefaction of small blood vessels in patients with HFpEF. Despite a reduced microvascular filtration coefficient, which is in keeping with microvascular rarefaction, the clearance of extravasated fluid in HFpEF is limited by an anatomically and functionally defective lymphatic system. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation Centre of Research Excellence Award

Oscillatory interstitial fluid pressure and velocity in a solid tumor with partial surface fluid leakage

This work investigates the interstitial fluid flow characteristics in a solid tumor with partial fluid leakage at the tumor surface subjected to oscillatory microvascular pressure. Solutions of the pore fluid pressure and velocity in a spherical tumor are obtained using the poroelasticity theory for small strains. It is found that partial fluid leakage at the tumor surface reduces the pore pressure drop and decreases the fluid velocity near the surface compared with those in a tumor with a fully leaking surface. Both the pore pressure and the fluid velocity decrease dramatically with an increase in the vascular frequency. The pore pressure at a vascular frequency of 1 Hz is two orders of magnitude smaller than the amplitude of the vascular pressure, and the fluid velocity at the same frequency is one order of magnitude smaller than that produced by the steady constant vascular pressure. The pore pressure amplitude may reach that of the vascular pressure under the steady state vascular pressure condition.

Conduit arterial wave reflection promotes pressure transmission but impedes hydraulic energy transmission to the microvasculature.

Current thinking suggests that wave reflection in arteries limits pulse pressure and hydraulic energy (HE) transmission to the microvasculature and that this protective effect reduces with advancing age. However, according to transmission line theory, pressure transmission (Tp) and reflection (R) coefficients are proportional (Tp = 1 + R), implying that wave reflection would promote rather than limit pressure transmission. We hypothesized that increasing distal pulse pressure (PPd) with age is instead related to increased proximal pulse pressure (PPp) and its forward component and that these are modulated by arterial compliance. A one-dimensional model of a fractal arterial tree containing 21 generations was constructed. Wave speed in each vessel was prescribed to achieve a uniform R at every junction, with changes in R achieved by progressively stiffening proximal or distal vessels. For both stiffening scenarios, decreasing reflection led to a decrease or no change in PPd when forward pressure or compliance were held constant, respectively, suggesting that wave reflection per se does not limit pressure transmission. Proximal pulse pressure, its forward component, and PPd increased with decreasing compliance; furthermore, proximal and distal pulse pressures were approximately proportional. With fixed compliance but decreasing reflection, HE transmission increased, whereas pressure transmission decreased, consistent with transmission line theory. In conclusion, wave reflection does not protect the microvasculature from high PPd; rather, PPp and PPd are modulated by arterial compliance, which reduces with age. Wave reflection has opposing effects on pressure and HE transmission; hence, the relative importance of pressure versus HE in contributing to microvascular damage warrants investigation.NEW & NOTEWORTHY With aging, a reduction in the stiffness gradient between elastic and muscular arteries is thought to reduce wave reflection in conduit arteries, leading to increased pulsatile pressure transmission into the microvasculature. This assumes that wave reflection limits pressure transmission in arteries. However, using a computational model, we showed that wave reflection promotes pulsatile pressure transmission, although it does limit hydraulic energy transmission. Increased microvascular pulse pressure with aging is instead related to decreasing arterial compliance.

Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function.

The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies.

Fructose Consumption Increases Blood Pressure and Induces Changes in Renal Microvascular Function

A drastic increase in fructose consumption over recent decades has been paralleled by a growing prevalence and incidence of hypertension, along with comorbidities, such as diabetes, renal failure, and cardiovascular disease. High fructose corn syrup is a commonly found ingredient in the Western diet. However, the use of fructose as a sweetener has been shown to promote salt‐sensitive hypertension. The mechanisms by which fructose induces an increase in blood pressure and its effect on renal microvascular function are not completely understood. The goal of this study was to understand the mechanisms that lead to fructose‐induced impairment in renal microvascular function and its relation to the development of hypertension. Salt‐resistant Sprague Dawley rats (8 weeks old) were kept on a low salt (LS; 0.4% NaCl) with or without addition of 20% fructose (FT) to the drinking water provided ad libitum. After two weeks control and FT‐treated groups were switched to a high salt (HS; 8% NaCl) diet. Blood pressure was monitored with surgically implanted telemetry devices. Electrolyte balance and changes in renal function were analyzed among experimental groups using urinary (24 hrs collections) and plasma samples. After two weeks on HS, animals were euthanized, and renal microvessels were isolated to assess renal smooth muscle cell (SMC) excitability. We found that FT‐treated animals experienced elevated systolic blood pressure at LS to compare with control, and this difference were significantly higher in HS‐treated groups (107 ± 3 vs 113 ± 3, and 114 ± 4 vs 131 ± 5, mmHg; LS vs LS+FT, and HS vs HS +FT, correspondingly). Furthermore, these changes inversely correlated with the shift in diuresis and electrolyte balance in HS‐treated animals (70 ± 15 vs 39 ± 15 ml/day, 284 ± 91 vs 123 ± 70 Na/Cre ratio, 36 ± 12 vs 14 ± 10 K/Cre ratio, 0.7 ± 0.4 vs 1.4 ± 0.3 Ca/Cre ratio, HS vs HS+FT correspondingly). No changes in albuminuria, compared with controls, were noted in any of the groups. Two‐photon microscopy analysis of the renal microvascular vasomotion revealed a decrease in amplitude of individual SMC Ca2+ activity at the resting, spontaneous state in both LS and HS FT‐treated groups. However, both amplitude and period of Ca2+ fluctuations in SMC was significantly increased when vessels were exposed to ET‐1 in HS+FT group. Moreover, the amplitude of ET‐1‐induced Ca2+ transient in FT‐treated animals were split into two distinct groups with either higher or lower amplitudes relative to control. Overall, renal microvessels exposed to FT revealed a significant decrease in spontaneous vasomotion, which is accompanying by high responsiveness to FT at the HS with significant decrease in frequency of spontaneous events. These effects further promote high sensitivity (above normal) to ET‐1 stimulation, cell damage and finally low responsiveness (below normal) in FT‐treated renal microvessels. In conclusion, these results indicate the detrimental effects of FT on intracellular Ca2+ homeostasis in SMC, renal microvascular function and blood pressure regulation under high dietary salt.Support or Funding InformationNational Institute of Health R35 HL135749 (to A.S.), Michael Keelan, Jr., MD, CVC Research Foundation Grant (to O.P.), and Advancing a Healthier Wisconsin Endowment (to J.D.I.)

Early hours in the development of high-altitude pulmonary edema: time course and mechanisms.

Clinically evident high-altitude pulmonary edema (HAPE) is characterized by severe cyanosis, dyspnea, cough, and difficulty with physical exertion. This usually occurs within 1-2 days of ascent often with the additional stresses of any exercise and hypoventilation of sleep. The earliest events in evolving HAPE progress through clinically silent and then minimally recognized problems. The most important of these events involves an exaggerated elevation of pulmonary artery (PA) pressure in response to the ambient hypoxia. Hypoxic pulmonary vasoconstriction (HPV) is a rapid response with several phases. The first phase in both resistance arterioles and venules occurs within 5-10 min. This is followed by a second phase that further raises PA pressure by another 100% over the next 2-8 h. Combined with vasoconstriction and likely an unevenness in the regional strength of HPV, pressures in some microvascular regions with lesser arterial constriction rise to a level that initiates greater filtration of fluid into the interstitium. As pressures continue to rise local lymphatic clearance rates are exceeded and interstitial fluid begins to accumulate. Beyond elevation of transmural pressure gradients there is a dynamic noninjurious relaxation of microvascular and epithelial cell-cell contacts and an increase in transcellular vesicular transport which accelerate leakage. At some point with further pressure elevation, damage occurs with breaks of the barrier and bleeding into the alveolar space, a late-stage situation termed capillary stress failure. Earlier before there is fluid accumulation, alveolar hypoxia and hyperventilation-induced hypocapnia reduce the capacity of the alveolar epithelium to reabsorb sodium and water back into the interstitial space. More modest ascent which slows the rate of rise in PA pressure and allows for adaptive remodeling of the microvasculature, drugs which lower PA pressure, and those that can enhance fluid reabsorption will all forestall the deleterious early rise of microvascular pressures and diminished active alveolar fluid reabsorption that precede and underlie the development of HAPE.

The role of vascular function on exercise capacity in health and disease.

Three sentinel parameters of aerobic performance are the maximal oxygen uptake ( ), critical power (CP) and speed of the kinetics following exercise onset. Of these, the latter is, perhaps, the cardinal test of integrated function along the O2 transport pathway from lungs to skeletal muscle mitochondria. Fast kinetics demands that the cardiovascular system distributes exercise-induced blood flow elevations among and within those vascular beds subserving the contracting muscle(s). Ideally, this process must occur at least as rapidly as mitochondrial metabolism elevates . Chronic disease and ageing create an O2 delivery (i.e. blood flow × arterial [O2 ], ) dependency that slows kinetics, decreasing CP and , increasing the O2 deficit and sowing the seeds of exercise intolerance. Exercise training, in contrast, does the opposite. Within the context of these three parameters (see Graphical Abstract), this brief review examines the training-induced plasticity of key elements in the O2 transport pathway. It asks how structural and functional vascular adaptations accelerate and redistribute muscle and thus defend microvascular O2 partial pressures and capillary blood-myocyte O2 diffusion across a ∼100-fold range of muscle values. Recent discoveries, especially in the muscle microcirculation and -to- heterogeneity, are integrated with the O2 transport pathway to appreciate how local and systemic vascular control helps defend kinetics and determine CP and in health and how vascular dysfunction in disease predicates exercise intolerance. Finally, the latest evidence that nitrate supplementation improves vascular and therefore aerobic function in health and disease is presented.