Microcirculation最新文献

Objective

During skin inflammation, inhibition of adhesion of regulatory T cells (Tregs) to the dermal microvascular endothelium leads to exacerbation of inflammation, evidence that the dermal endothelium is a key target of the anti-inflammatory actions of Tregs. The aim of this study was to investigate the capacity of Tregs to control the expression of endothelial adhesion molecules in inflamed and resting skin.

Methods

Treg function was assessed in a two-challenge contact hypersensitivity (CHS) model, measuring dermal adhesion molecule expression via imaging of cleared skin. Treg depletion was achieved using Foxp3^DTR mice.

Results

CHS induced upregulation of E-selectin and ICAM-1 but not P-selectin and VCAM-1. Elimination of Tregs following CHS challenge resulted in exacerbated skin inflammation and enhanced expression of E-selectin, P-selectin and ICAM-1 in the dermal microvasculature. Multiphoton imaging revealed that at this phase of the response, Tregs were enriched near blood vessels and underwent dynamic migration adjacent to the microvasculature. Additionally, in skin that was not undergoing hapten challenge, absence of Tregs also resulted in upregulation of E-selectin and ICAM-1 in skin vessels.

Conclusions

These observations demonstrate that the microvascular endothelium is a target of the anti-inflammatory actions of Tregs in the skin, both during CHS and in steady-state skin.

Neuropeptide Y (NPY) is a sympathetic co-transmitter that mediates vasoconstriction. However, there is evidence that it may also mediate dilation through a nitric oxide (NO)-dependent mechanism.

Objective

We used a swine model to examine how NPY influences cerebral vascular regulation and hypothesized that NPY would elicit both vasoconstrictor and vasodilatory effects, and that such effects would be modulated partially by NO signaling.

Methods

Briefly, cerebral perfusion and blood pressure were monitored during intracarotid saline or NPY infusion (0.1 μg/kg) in the presence and absence of NO synthase (NOS) inhibition (N^G-nitro-l-arginine methyl ester; 0.35 mg/kg/min). Separately, Y1 receptor distribution (immunohistochemistry) and vasomotor responses to intra- and extraluminal NPY under control and NOS inhibition conditions were examined in isolated arteries.

Results

Intracarotid NPY infusions elicited transient dilation that was blocked by NOS inhibition. In isolated pial arteries, distinct populations of NPY-Y1 receptors were observed on both the vascular smooth muscle (VSM) and endothelium. Extraluminal application of NPY elicited vasoconstriction, while intraluminal delivery elicited vasodilation. NOS inhibition enhanced the magnitude of vasoconstriction in isolated pial arteries. Endothelial denudation, Y1 receptor antagonism, and NOS inhibition each blunted NPY-induced vasodilation.

Conclusion

These data suggest both vasoconstrictor and vasodilatory effects of NPY are modulated partially by NO signaling.

Objective

Hypertension is related to the pathogenesis of microvascular dysfunction. Renal denervation is a guideline-endorsed intervention for the management of uncontrolled hypertension. However, the effect of renal denervation on skin capillary density, as assessed by nailfold capillaroscopy, is unknown.

Methods

Individuals with stage I/II uncontrolled hypertensions were enrolled and allocated to either undergo renal denervation or serve as controls. Nailfold capillaroscopy was performed at baseline and at 12 months. Furthermore, the albumin to creatinine ratio (ACR) and office/ambulatory blood pressure (BP) levels were monitored throughout the study.

Results

A total of 45 individuals (28 renal denervation, 17 control) were enrolled in our study. No difference was found in baseline capillary density. At 12 months, all patients had controlled BP, while the denervation arm had a significantly greater number of capillaries, compared with control (90.9 ± 14.0 vs. 82.5 ± 10.6 capillaries/mm²; p = 0.036). However, the change from baseline capillary density was not significantly different between groups (4.6 ± 6.1 vs. 1.39 ± 8.8 capillaries/mm²; p = 0.150). Moreover, the change of ACR was not different between groups (−2.7 ± 13.8 vs. 0.46 ± 5.2; p = 0.365).

Conclusion

In patients with uncontrolled stage I/II hypertension, renal denervation may have a beneficial effect on skin capillary density.

Objective

This study investigates the effects of hemodynamic factors on blood cell suspension flows and their properties in curved microvessels. A parametric study is employed to compare these properties between curved and straight vessels.

Methods

A 3D fluid solver coupled with a cell membrane modeling framework via the immersed boundary method was used to simulate cell-resolved blood flow in straight and curved vessels featuring a 90° bend with moderate curvature.

Results

Blood flow in curved vessels shows lower and higher shear rates in the inner and outer bulk regions, respectively, compared to straight vessels. Asymmetry in hematocrit profiles is linked to less dense suspensions, smaller diameters, and higher Capillary numbers, while the maximum velocity location remains consistent with straight vessels. At physiological shear rates, moderate curvatures, and large diameters, curvature has minimal impact on apparent viscosity. However, diffusivity is elevated at the center of curved vessels compared to straight ones.

Conclusions

This study reveals new insights into blood suspension flows in curved microvessels with a 90° bend, highlighting key differences from straight vessels under certain hemodynamic conditions. These findings lay the groundwork for future research on realistic microvessel geometries and their implications.

Objective

Cell-free hemoglobin (CFH) is released into the circulation during sepsis where it can redox cycle from the ferrous 2+ to ferric 3+ and disrupt endothelial function, but the mechanisms of CF-mediated endothelial dysfunction are unknown. We hypothesized that oxidized CFH induces mitochondrial dysfunction via the mitochondrial permeability transition pore (mPTP) in pulmonary endothelial cells, leading to the release of mitochondrial DNA (mtDNA).

Methods

Human lung microvascular endothelial cells were treated with CFH2+/CFH3+. We measured mitochondrial mPTP activation (flow cytometry), network and mass (immunostaining), structure (electron microscopy), mtDNA release (PCR), and oxygen consumption rate (OCR; Seahorse). Plasma from critically ill patients and conditioned cell media were quantified for mtDNA and CFH.

Results

CFH3+ disrupted the mitochondrial network, activated the mPTP (1434 (874–1642) vs. 2302 (1729–2654) mean fluorescent intensity, p = 0.02), increased the spare respiratory capacity (30.61 (29.36–37.78) vs. 7.83 (3.715–10.63) OCR, p = 0.004), and caused the release of mtDNA. CFH was associated with circulating mtDNA (R² = 0.1912, p = 0.0077) in plasma from critically ill patients.

Conclusion

CFH3+, not CFH2+, is the primary driver of CFH-induced lung microvascular mitochondrial dysfunction. Activation of the mPTP and the release of mtDNA are a feature of CFH3+ mediated injury.

Objective

The convection effect of plasma flow on gas transport in the microcirculation has been a controversial topic in the literature. We aim to clarify this concern via thorough and rigorous analysis of the oxygen release process from red blood cells (RBCs) to the surrounding tissue.

Methods

We develop a comprehensive model that considers the plasma flow, RBC deformation, oxygen transport and oxygen-hemoglobin reaction kinetics. The boundary integral and lattice Boltzmann methods are employed in the numerical solutions. In particular, the oxygen fluxes due to plasma convection and mass diffusion are separately calculated along the capillary wall for further comparison.

Results

Our results show that the most significant diffusive flux occurs in the narrow gap between the RBC side surface and the capillary wall and the diffusive flux is primarily directed outward, which favors oxygen release into the surrounding tissue. Furthermore, although the axial convective flux is the most profound in magnitude, it contributes little to the overall blood-to-tissue oxygen transport in the radial direction. The radial convective flux also has a larger magnitude compared to the diffusive oxygen flux, but is limited to two small areas and to opposite directions. This results in a negligible net effect of the plasma convection compared to the diffusive flux on the overall oxygen transport. This observation is further confirmed by comparing the oxygen distributions and diffusive fluxes from simulations with and without considering the plasma convection flow relative to RBCs. Moreover, we revisit the Peclet number definition and propose that different characteristic length scales should be adopted for oxygen diffusion and convection in capillaries. The revised Peclet number has a value three orders of magnitude lower than that from the classical Peclet number definition.

Conclusions

Our simulation results show that the influence of plasma convection on the overall oxygen transport can be neglected in typical microcirculation situations. This is consistent with the revised Peclet number value, suggesting that the revised Peclet number can better reflect the relative importance of convection and diffusion mechanisms in microvascular gas transport.

Objective

Mesenchymal stem cells (MSCs) represent an attractive option as an endothelial cell (EC) source for regenerative medicine therapies. However, the differentiation of MSCs toward an ECs phenotype can be regulated by a complex and dynamic microenvironment, including specific growth factors as well as local mechanical cues. The objective of this work was to evaluate whether Physiologically-modeled dynamic stimulation (PMDS) characterized by continuous variability in pulse frequencies mimicking the dynamic temporal range of cardiac function would enhance MSC differentiation toward ECs compared to a constant frequency stimulation.

Methods

Mesenchymal stem cells were grown in a complex growth factor cocktail versus standard culture media to initiate the endothelial differentiation process, then subsequently exposed to PMDS that vary in duration and constant flow (CF) at a fixed 10 dynes/cm² shear stress and 1.3 Hz frequency.

Results

Both PMDS and media type strongly influence cell differentiation and function. Cells were shown to significantly upregulate eNOS activity and displayed lower TNF-a induced leukocyte adhesion compared to cells cultured under CF, consistent with a more quiescent ECs phenotype that regulates anti-inflammatory and anti-thrombotic states.

Conclusion

These findings suggest that the dynamic microenvironment created by perfusion, in contrast to constant frequency, combined with growth factors, enhances MSCs differentiation toward a vascular endothelial-like phenotype.