Isolated Fragments of Intact Microvessels: Tissue Vascularization, Modeling, and Therapeutics.

The microvasculature is integral to nearly every tissue in the body, providing not only perfusion to and from the tissue, but also homing sites for immune cells, cellular niches for tissue dynamics, and cooperative interactions with other tissue elements. As a microtissue itself, the microvasculature is a composite of multiple cell types exquisitely organized into structures (individual vessel segments and extensive vessel networks) capable of considerable dynamics and plasticity. Consequently, it has been challenging to include a functional microvasculature in assembled or fabricated tissues. Isolated fragments of intact microvessels, which retain the cellular composition and structures of native microvessels, are proving effective in a variety of vascularization applications including tissue in vitro disease modeling, vascular biology, mechanistic discovery, and tissue prevascularization in regenerative therapeutics and grafting. In this review, we will discuss the importance of recapitulating native tissue biology and the successful vascularization applications of isolated microvessels.

Cell Chirality of Micropatterned Endometrial Microvascular Endothelial Cells.

Chirality is an intrinsic cellular property that describes cell polarization biases along the left-right axis, apicobasal axis, or front-rear axes. Cell chirality plays a significant role in the arrangement of organs in the body as well as in the orientation of organelles, cytoskeletons, and cells. Vascular networks within the endometrium, the mucosal inner lining of the uterus, commonly display spiral architectures that rapidly form across the menstrual cycle. Herein, the role of endometrial-relevant extracellular matrix stiffness, composition, and soluble signals on endometrial endothelial cell chirality is systematically examined using a high-throughput microarray. Endometrial endothelial cells display marked patterns of chirality as individual cells and as cohorts in response to substrate stiffness and environmental cues. Vascular networks formed from endometrial endothelial cells also display shifts in chirality as a function of exogenous hormones. Changes in cellular-scale chirality correlate with changes in vascular network parameters, suggesting a critical role for cellular chirality in directing endometrial vessel network organization.

Quantitative study of spatial and temporal variation in retinal capillary network perfusion in rat eye by in vivo confocal imaging.

Microvascular dysfunction is the underlying pathological process in many systemic diseases. However, investigation into its pathogenesis is impeded by the accessibility and complexity of the microvasculature within different organs, particularly for the central nervous system. The retina as an extension of the cerebrum provides a glimpse into the brain through which the microvasculature can be observed. Two major questions remain unanswered: How do the microvessels regulate spatial and temporal delivery to satisfy the varying cellular demands, and how can we quantify blood perfusion in the 3D capillary network? Here, quantitative measurements of red blood cell (RBC) speed in each vessel in the field were made in the in vivo rat retinal capillary network using an ultrafast confocal technique with fluorescently labelled RBCs. Retinal RBC speed and number were found to vary remarkably between microvessels ranging from 215 to 6641 microns per second with significant variations spatially and temporally. Overall, the RBC speed was significantly faster in the microvessels in the superficial retina than in the deep retina (estimated marginal means of 2405 ± 238.2 µm/s, 1641 ± 173.0 µm/s respectively). These observations point to a highly dynamic nature of microvasculature that is specific to its immediate cellular environment and is constantly changing.

Angiogenic Microvascular Wall Shear Stress Patterns Revealed Through Three-dimensional Red Blood Cell Resolved Modeling.

The wall shear stress (WSS) exerted by blood flowing through microvascular capillaries is an established driver of new blood vessel growth, or angiogenesis. Such adaptations are central to many physiological processes in both health and disease, yet three-dimensional (3D) WSS characteristics in real angiogenic microvascular networks are largely unknown. This marks a major knowledge gap because angiogenesis, naturally, is a 3D process. To advance current understanding, we model 3D red blood cells (RBCs) flowing through rat angiogenic microvascular networks using state-of-the-art simulation. The high-resolution fluid dynamics reveal 3D WSS patterns occurring at sub-endothelial cell (EC) scales that derive from distinct angiogenic morphologies, including microvascular loops and vessel tortuosity. We identify the existence of WSS hot and cold spots caused by angiogenic surface shapes and RBCs, and notably enhancement of low WSS regions by RBCs. Spatiotemporal characteristics further reveal how fluctuations follow timescales of RBC "footprints." Altogether, this work provides a new conceptual framework for understanding how shear stress might regulate EC dynamics in vivo.

Estimation of shear stress heterogeneity along capillary segments in angiogenic rat mesenteric microvascular networks.

OBJECTIVE: Fluid shear stress is thought to be a regulator of endothelial cell behavior during angiogenesis. The link, however, requires an understanding of stress values at the capillary level in angiogenic microvascular networks. Critical questions remain. What are the stresses? Do capillaries experience similar stress magnitudes? Can variations explain vessel-specific behavior? The objective of this study was to estimate segment-specific shear stresses in angiogenic networks. METHODS: Images of angiogenic networks characterized by increased vascular density were obtained from rat mesenteric tissues stimulated by compound 48/80-induced mast cell degranulation. Vessels were identified by perfusion of a 40 kDa fixable dextran prior to harvesting and immunolabeling for PECAM. Using a network flow-based segment model with physiologically relevant parameters, stresses were computed per vessel for regions across multiple networks. RESULTS: Stresses ranged from 0.003 to 2328.1 dyne/cm2 and varied dramatically at the capillary level. For all regions, the maximum segmental shear stresses were for capillary segments. Stresses along proximal capillaries branching from arteriole inlets were increased compared to stresses along capillaries in more distal regions. CONCLUSIONS: The results highlight the variability of shear stresses along angiogenic capillaries and motivate new discussions on how endothelial cells may respond in vivo to segment-specific microenvironment during angiogenesis.

Hydrogels to Recapture Extracellular Matrix Cues That Regulate Vascularization.

The ECM (extracellular matrix) is a 3-dimensional network that supports cellular responses and maintains structural tissue integrity in healthy and pathological conditions. The interactions between ECM and cells trigger signaling cascades that lead to phenotypic changes and structural and compositional turnover of the ECM, which in turn regulates vascular cell behavior. Hydrogel biomaterials are a powerful platform for basic and translational studies and clinical applications due to their high swelling capacity and exceptional versatility in compositions and properties. This review highlights recent developments and uses of engineered natural hydrogel platforms that mimic the ECM and present defined biochemical and mechanical cues for vascularization. Specifically, we focus on modulating vascular cell stimulation and cell-ECM/cell-cell interactions in the microvasculature that are the established biomimetic microenvironment.

Direct Blood Cell Flow Imaging in Microvascular Networks.

Blood flow dynamics in microvascular networks are intimately related to the health of tissues and organs. While numerous imaging modalities and techniques have been developed to assess blood flow dynamics for various applications, their utilization has been hampered by limited imaging speed and indirect quantification of blood flow dynamics. Here, direct blood cell flow imaging (DBFI) is demonstrated that provides visualization of individual motions of blood cells over a field of 0.71 mm × 1.42 mm with a time resolution of 0.69 ms (1450 frames s-1 ) without using any exogenous agents. DBFI enables precise dynamic analysis of blood cell flow velocities and fluxes in various vessels over a large field, from capillaries to arteries and veins, with unprecedented time resolution. Three exemplary applications of DBFI, quantification of blood flow dynamics of 3D vascular networks, analysis of heartbeat induced blood flow dynamics, and analysis of blood flow dynamics of neurovascular coupling, illustrate the potential of this new imaging technology.

Shear stress and intravascular pressure effects on vascular dynamics: two-phase blood flow in elastic microvessels accounting for the passive stresses.

We study the steady hemodynamics in physiological elastic microvessels proposing an advanced fluid-structure interaction model. The arteriolar tissue is modeled as a two-layer fiber-reinforced hyperelastic material representing its Media and Adventitia layers. The constitutive model employed (Holzapfel et al. in J Elast 61:1-48, 2000) is parametrized via available data on stress-strain experiments for arterioles. The model is completed by simulating the blood/plasma flow in the lumen, using the thixotropic elasto-viscoplastic model in its core, and the linear Phan-Thien and Tanner viscoelastic model in its annular part. The Cell-Free Layer (CFL) and the Fåhraeus and Fåhraeus-Lindqvist effects are considered via analytical expressions based on experimental data (Giannokostas et al. in Materials (Basel) 14:367, 2021b). The coupling between tissue deformation and blood flow is achieved through the experimentally verified pressure-shear hypothesis (Pries et al. Circ Res 77:1017-1023, 1995). Our calculations confirm that the increase in the reference inner radius produces larger expansion. Also, by increasing the intraluminal pressure, the thinning of the walls is more pronounced and it may reach 40% of the initial thickness. Comparing our predictions with those in rigid-wall microtubes, we conclude that apart from the vital importance of vasodilation, there is an up to 25% reduction in wall shear stress. The passive vasodilation contributes to the decrease in the tissue stress fields and affects the hemodynamic features such as the CFL thickness, reducing the plasma layer when blood flows in vessels with elastic walls, in quantitative agreement with previous experiments. Our calculations verify the correctness of the pressure-shear hypothesis but not that of the Laplace law.

Structural Features of Microvascular Networks Trigger Blood Flow Oscillations.

We analyse mathematical models in order to understand how microstructural features of vascular networks may affect blood flow dynamics, and to identify particular characteristics that promote the onset of self-sustained oscillations. By focusing on a simple three-node motif, we predict that network "redundancy", in the form of a redundant vessel connecting two main flow-branches, together with differences in haemodynamic resistance in the branches, can promote the emergence of oscillatory dynamics. We use existing mathematical descriptions for blood rheology and haematocrit splitting at vessel branch-points to construct our flow model; we combine numerical simulations and stability analysis to study the dynamics of the three-node network and its relation to the system's multiple steady-state solutions. While, for the case of equal inlet-pressure conditions, a "trivial" equilibrium solution with no flow in the redundant vessel always exists, we find that it is not stable when other, stable, steady-state attractors exist. In turn, these "nontrivial" steady-state solutions may undergo a Hopf bifurcation into an oscillatory state. We use the branch diameter ratio, together with the inlet haematocrit rate, to construct a two-parameter stability diagram that delineates regimes in which such oscillatory dynamics exist. We show that flow oscillations in this network geometry are only possible when the branch diameters are sufficiently different to allow for a sufficiently large flow in the redundant vessel, which acts as the driving force of the oscillations. These microstructural properties, which were found to promote oscillatory dynamics, could be used to explore sources of flow instability in biological microvascular networks.

Photoacoustic imaging for microcirculation.

Microcirculation facilitates the blood-tissue exchange of nutrients and regulates blood perfusion. It is, therefore, essential in maintaining tissue health. Aberrations in microcirculation are potentially indicative of underlying cardiovascular and metabolic pathologies. Thus, quantitative information about it is of great clinical relevance. Photoacoustic imaging (PAI) is a capable technique that relies on the generation of imaging contrast via the absorption of light and can image at micron-scale resolution. PAI is especially desirable to map microvasculature as hemoglobin strongly absorbs light and can generate a photoacoustic signal. This paper reviews the current state of the art for imaging microvascular networks using photoacoustic imaging. We further describe how quantitative information about blood dynamics such as the total hemoglobin concentration, oxygen saturation, and blood flow rate is obtained using PAI. We also discuss its importance in understanding key pathophysiological processes in neurovascular, cardiovascular, ophthalmic, and cancer research fields. We then discuss the current challenges and limitations of PAI and the approaches that can help overcome these limitations. Finally, we provide the reader with an overview of future trends in the field of PAI for imaging microcirculation.

The efficacy of a paeoniflorin-sodium alginate-gelatin skin scaffold for the treatment of diabetic wound: An in vivo study in a rat model.

OBJECTIVE: To investigate the efficacy of a paeoniflorin-sodium alginate (SA)-gelatin skin scaffold for treating diabetic wound in a rat model. METHODS: Bioinks were prepared using various percentages of paeoniflorin in the total weight of a solution containing SA and gelatin. Skin scaffolds containing 0%, 1%, 3%, 5%, and 10% paeoniflorin were printed using 3D bioprinting technology, and scaffold microstructure was observed with scanning electron microscopy. Skin scaffolds were then used in rats with diabetic wounds. H&E staining, Masson staining, and immunohistochemical staining for IL-1ß and CD31 were performed on days 7 and 14. RESULTS: All skin scaffolds had a mesh-like structure with uniform pore distribution. Wounds healed well in each group, with the 1% and 3% groups demonstrating the most complete healing. H&E staining showed that skin accessory organs had appeared in each group. On day 7, collagen deposition in the 3% group was higher than in the other groups (P＜0.05), and IL-1ß infiltration was lower in the 10% group than in the 3% group (P = 0.002). On day 14, IL-1ß infiltration was not significantly different between the 10% and 3% groups (P = 0.078). The CD31 level was higher in the 3% group than in the other groups on days 7 and 14 (P＜0.05). CONCLUSION: A 3% paeoniflorin-SA-gelatin skin scaffold promoted the healing of diabetic wounds in rats. This scaffold promoted collagen deposition and microvascular regeneration and demonstrated anti-inflammatory properties, suggesting that this scaffold type could be used to treat diabetic wounds.

A computational study of red blood cell deformability effect on hemodynamic alteration in capillary vessel networks.

Capillary blood vessels, the smallest vessels in the body, form an intricate network with constantly bifurcating, merging and winding vessels. Red blood cells (RBCs) must navigate through such complex microvascular networks in order to maintain tissue perfusion and oxygenation. Normal, healthy RBCs are extremely deformable and able to easily flow through narrow vessels. However, RBC deformability is reduced in many pathological conditions and during blood storage. The influence of reduced cell deformability on microvascular hemodynamics is not well established. Here we use a high-fidelity, 3D computational model of blood flow that retains exact geometric details of physiologically realistic microvascular networks, and deformation of every one of nearly a thousand RBCs flowing through the networks. We predict that reduced RBC deformability alters RBC trafficking with significant and heterogeneous changes in hematocrit. We quantify such changes along with RBC partitioning and lingering at vascular bifurcations, perfusion and vascular resistance, and wall shear stress. We elucidate the cellular-scale mechanisms that cause such changes. We show that such changes arise primarily due to the altered RBC dynamics at vascular bifurcations, as well as cross-stream migration. Less deformable cells tend to linger less at majority of bifurcations increasing the fraction of RBCs entering the higher flow branches. Changes in vascular resistance also seen to be heterogeneous and correlate with hematocrit changes. Furthermore, alteration in RBC dynamics is shown to cause localized changes in wall shear stress within vessels and near vascular bifurcations. Such heterogeneous and focal changes in hemodynamics may be the cause of morphological abnormalities in capillary vessel networks as observed in several diseases.

Dependence of red blood cell dynamics in microvessel bifurcations on the endothelial surface layer's resistance to flow and compression.

Red blood cells (RBCs) make up 40-45% of blood and play an important role in oxygen transport. That transport depends on the RBC distribution throughout the body, which is highly heterogeneous. That distribution, in turn, depends on how RBCs are distributed or partitioned at diverging vessel bifurcations where blood flows from one vessel into two. Several studies have used mathematical modeling to consider RBC partitioning at such bifurcations in order to produce useful insights. These studies, however, assume that the vessel wall is a flat impenetrable homogeneous surface. While this is a good first approximation, especially for larger vessels, the vessel wall is typically coated by a flexible, porous endothelial glycocalyx or endothelial surface layer (ESL) that is on the order of 0.5-1 µm thick. To better understand the possible effects of this layer on RBC partitioning, a diverging capillary bifurcation is analyzed using a flexible, two-dimensional model. In addition, the model is also used to investigate RBC deformation and RBC penetration of the ESL region when ESL properties are varied. The RBC is represented using interconnected viscoelastic elements. Stokes flow equations (viscous flow) model the surrounding fluid. The flow in the ESL is modeled using the Brinkman approximation for porous media with a corresponding hydraulic resistivity. The ESL's resistance to compression is modeled using an osmotic pressure difference. One cell passes through the bifurcation at a time, so there are no cell-cell interactions. A range of physiologically relevant hydraulic resistivities and osmotic pressure differences are explored. Decreasing hydraulic resistivity and/or decreasing osmotic pressure differences (ESL resistance to compression) produced four behaviors: (1) RBC partitioning nonuniformity increased slightly; (2) RBC deformation decreased; (3) RBC velocity decreased relative to blood flow velocity; and (4) RBCs penetrated more deeply into the ESL. Decreasing the ESL's resistance to flow and/or compression to pathological levels could lead to more frequent cell adhesion and clotting as well as impaired vascular regulation due to weaker ATP and nitric oxide release. Potential mechanisms that can contribute to these behaviors are also discussed.

Brief Report: Retinal Microvasculature and Immune Restoration Among South Eastern Asian Patients With HIV/AIDS Over a 9-Month Antiretroviral Therapy.

BACKGROUND: Longitudinal evidence on retinal microvasculature and subsequent systemic inflammatory alteration is lacking. We investigated the association between retinal microvasculature and immune response among patients with HIV/AIDS over a 9-month antiretroviral therapy. METHODS: We conducted a prospective cohort study on patients with HIV/AIDS at Singapore Communicable Disease Centre since June 2011. We recruited all eligible patients and then reviewed them every 3 months over a 9-month follow-up, including performing blood tests (CD4+/CD8+ T-cell counts and HIV viral load), blood pressure, anthropometry measurements, and retinal photography at each visit. We assessed retinal vascular indexes using a semiautomated computer-based program. Finally, we applied a linear mixed model to analyze associations between baseline retinal vascular indexes and 9-month changes of CD4+/CD8+ T-cell counts and HIV viral load throughout study observation, after adjusting for major confounders. RESULTS: We found that narrower arteriolar caliber (per 10 µm decrease), wider venular caliber (per 10 µm increase), and larger arteriolar branching angle (per 10° increase) in the retina assessed at baseline were significantly associated with 9-month reductions in CD4+ T-cell count by 52.97 cells/µL (P = 0.006), 33.55 cells/µL (P = 0.01), and 39.09 cells/µL (P = 0.008), accordingly. CONCLUSION: Patients with HIV/AIDS with a suboptimal retinal microvascular morphology tended to fail immune restoration undertaking a 9-month antiretroviral therapy.

Targeting Interleukin-10 Restores Graft Microvascular Supply and Airway Epithelium in Rejecting Allografts.

Interleukin-10 (IL-10) is a vital regulatory cytokine, which plays a constructive role in maintaining immune tolerance during an alloimmune inflammation. Our previous study highlighted that IL-10 mediated immunosuppression established the immune tolerance phase and thereby modulated both microvascular and epithelial integrity, which affected inflammation-associated graft malfunctioning and sub-epithelial fibrosis in rejecting allografts. Here, we further investigated the reparative effects of IL-10 on microvasculature and epithelium in a mouse model of airway transplantation. To investigate the IL-10 mediated microvascular and epithelial repair, we depleted and reconstituted IL-10, and monitored graft microvasculature, airway epithelium, and associated repair proteins. Our data demonstrated that both untreated control allografts and IL-10 (-) allografts showed a significant early (d6) increase in microvascular leakiness, drop-in tissue oxygenation, blood perfusion, and denuded airway epithelium, which is associated with loss of adhesion protein Fascin-1 and ß-catenin on vascular endothelial cells at d10 post-transplantation. However, IL-10 (+) promotes early microvascular and airway epithelial repair, and a proportional increase in endothelial Fascin-1, and ß-catenin at d10 post-transplantation. Moreover, airway epithelial cells also express a significantly higher expression of FOXJ1 and ß-catenin in syngrafts and IL-10 (+) allografts as compared to IL-10 (-) and untreated controls at d10 post-transplantation. Collectively, these findings demonstrated that IL-10 mediated microvascular and epithelial changes are associated with the expression of FOXJ1, ß-catenin, and Fascin-1 proteins on the airway epithelial and vascular endothelial cells, respectively. These findings establish a potential reparative modulation of IL-10 associated microvascular and epithelial repair, which could provide a vital therapeutic strategy to facilitate graft repair in clinical settings.

Acute heat exposure improves microvascular function in skeletal muscle of aged adults.

Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. We hypothesized that acute hot water immersion would improve endothelial-dependent, but not endothelial-independent vasodilation in the microcirculation of the vastus lateralis muscle in healthy aged adults. Participants (70 ± 5 yr) were immersed for 60 min in thermoneutral (36°C) or hot (40°C) water. Ninety minutes following immersion, skeletal muscle microdialysis was used to bypass the cutaneous circulation and directly assess endothelial-dependent and endothelial-independent vasodilation by measuring the local hyperemic response to graded infusions of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. The hyperemic response to 27.5 mM ACh did not differ between thermal conditions (P = 0.9). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, 43.9 ± 23.2 mL/min/100 g vs. hot water immersion, 66.5 ± 25.5 mL/min/100 g; P < 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions (P = 0.3) but was increased following hot water immersion with the infusion of 42 mM SNP (thermoneutral immersion, 48.8 ± 25.6 mL/min/100 g vs. hot water immersion, 90.7 ± 53.5 mL/min/100 g; P < 0.01). These data suggest that acute heat exposure improves microvascular function in skeletal muscle of aged humans.NEW & NOTEWORTHY Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. Using the microdialysis technique to bypass the cutaneous circulation, we demonstrated that heat exposure improves endothelial-dependent and endothelial-independent vasodilation in the microcirculation of skeletal muscle in aged humans.

Microcirculatory and glycocalyx properties are lowered by high-salt diet but augmented by Western diet in genetically heterogeneous mice.

Many individuals in industrialized societies consume a high-salt, Western diet(WD); however, the effects of this diet on microcirculatory properties and glycocalyx barrier function are unknown. Young genetically heterogeneous male and female mice underwent 12 wk of normal chow (NC) diet, NC diet with 4% salt (NC4%), Western diet (WD), or WD with 4% salt (WD4%). Microcirculatory properties and glycocalyx barrier function were evaluated in the mesenteric microcirculation, using an intravital microscope equipped with an automated capture and analysis system. Total microvascular density summed across 4- to 25-µm microvessel segment diameters was lower in NC4% than in NC and WD (P < 0.05). Perfused boundary region (PBR), a marker of glycocalyx barrier function, averaged across 4- to 25-µm microvessel segment diameters was similar between NC and NC4%, as well as between WD and WD4% (P > 0.05). PBR was lower in WD and WD4% than in NC and NC4% (P < 0.05), indicating augmented glycocalyx barrier function in WD and WD4%. There were strong, inverse relationships between PBR and adiposity and blood glucose (r = -0.44 to -0.61, P < 0.05). In summary, NC4% induces deleterious effects on microvascular density, whereas WD augments glycocalyx barrier function. Interestingly, the combination of high-salt, Western diet in WD4% resulted in lower total microvascular density like NC4% and augmented glycocalyx barrier function like WD. These data suggest distinct microcirculatory adaptations to high-salt and Western diets that coincide when these diets are combined in young genetically heterogeneous male and female mice.NEW & NOTEWORTHY Many individuals in industrialized societies consume a combination of high-salt and Western diet; however, the effects of this diet on microcirculatory and glycocalyx properties are unknown. This study reveals that a high-salt diet lowers microcirculatory and glycocalyx properties, whereas a Western diet augments glycocalyx barrier function and thickness. Taken together, these data indicate that there are distinct microcirculatory adaptations to high-salt and Western diets that coincide when high-salt and Western diets are combined.

Effects of microsomal prostaglandin E synthase-1 inhibition on resistance artery tone in patients with end stage kidney disease.

BACKGROUND: The microvasculature is a target organ for the early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition and concomitant reduction of PGE2 in vascular beds are of interest. EXPERIMENTAL APPROACH: The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (diameter: 100-400 µm) from patients with end stage kidney disease (ESKD) and controls (Non-ESKD) were studied using wire-myography in combination with immunological and mass-spectrometry based analyses. KEY RESULTS: Inhibition of mPGES-1 in arteries from ESKD patients and Non-ESKD controls significantly reduced adrenergic vasoconstriction, which was unaffected by the COX-2 inhibitors NS-398 and Etoricoxib, or by the COX-1/COX-2 inhibitor Indomethacin tested in Non-ESKD controls. However, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition. In IL-1ß treated arteries, inhibition of mPGES-1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX-2 inhibition blocked the formation of both prostaglandins. Blockade of PGI2 signalling with an IP receptor antagonist did not restore the reduced adrenergic constriction, neither did blocking PGE2 -EP4 or signalling through PPARγ. A biphasic effect was observed for PGE2 , inducing dilatation at nanomolar and constriction at micromolar concentrations. Immunohistochemistry demonstrated expression of mPGES-1, COX-1, PGIS, weak expression for COX-2, as well as receptor expression for PGE2 (EP1-4), thromboxane (TP) and PGI2 (IP) in ESKD and Non-ESKD. CONCLUSION: Our study demonstrates vasodilating effects following mPGES-1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 are involved.

Contributions of endothelin-1 and l-arginine to blunted cutaneous microvascular function in young, black women.

Non-Hispanic black (BL) individuals have the greatest prevalence of cardiovascular disease (CVD), relative to other racial/ethnic groups (e.g., non-Hispanic white population; WH), which may be secondary to blunted vascular function. Although women typically present with reduced CVD relative to men of the same racial/ethnic group, the prevalence is similar between BL women and men though the mechanisms differ. This study hypothesized that reduced microvascular function in young, BL women is associated with endothelin-1 (ET-1) overactivity or insufficient l-arginine bioavailability. Nine BL and nine WH women participated (age: 20 ± 2 vs. 22 ± 2 yr). Cutaneous microvascular function was assessed during 39°C local heating, whereas lactated Ringer's (control), BQ-123 (ET-1 receptor type A antagonist), BQ-788 (ET-1 receptor type B antagonist), or l-arginine were infused via intradermal microdialysis to modify cutaneous vascular conductance (CVC). Subsequent infusion of Nω-nitro-l-arginine methyl ester allowed for quantification of the nitric oxide (NO) contribution to vasodilation, whereas combined sodium nitroprusside and 43°C heating allowed for normalization to maximal CVC (%CVCmax). BL women had blunted %CVCmax and NO contribution to dilation during the 39°C plateau (P < 0.027 for both). BQ-123 improved this response through augmented NO-mediated dilation (P < 0.048 for both). BQ-788 and l-arginine did not alter the CVC responses (P > 0.835 for both) or the NO contribution (P > 0.371 for both). Cutaneous microvascular function is reduced in BL women, and ET-1 receptor type A may contribute to this reduced function. Further research is needed to better characterize these mechanisms in young, BL women.NEW & NOTEWORTHY Cardiovascular disease remains a burden in the United States non-Hispanic black (BL) population, although its manifestation through blunted vasodilation in this population is different between men and women. Accordingly, this study determined that reduced microvascular function in young, BL women may be partially controlled by endothelin-1 (ET-1) type A receptors, although neither type B receptors nor insufficient l-arginine bioavailability seems to contribute to this response. Accordingly, further research is needed to better characterize these ET-1 related mechanisms and illuminate other pathways that may contribute to this disparate vascular function in young, BL women.

Inflammation in Coronary Microvascular Dysfunction.

Chronic low-grade inflammation is involved in coronary atherosclerosis, presenting multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure and sudden cardiac death. Coronary microvasculature consists of vessels with a diameter less than 500 µm, whose potential structural and functional abnormalities can lead to inappropriate dilatation and an inability to meet the required myocardium oxygen demands. This review focuses on the pathogenesis of coronary microvascular dysfunction and the capability of non-invasive screening methods to detect the phenomenon. Anti-inflammatory agents, such as statins and immunomodulators, including anakinra, tocilizumab, and tumor necrosis factor-alpha inhibitors, have been assessed recently and may constitute additional or alternative treatment approaches to reduce cardiovascular events in atherosclerotic heart disease characterized by coronary microvascular dysfunction.