Healthy Vasculature Research Articles

Changes in Retinal Blood Flow in Response to an Experimental Increase in IOP in Healthy Participants as Assessed With Doppler Optical Coherence Tomography.

PurposeBlood flow autoregulation is an intrinsic mechanism of the healthy retinal vasculature to keep blood flow constant when ocular perfusion pressure (OPP) is changed. In the present study, we set out to investigate retinal blood flow in response to an experimental decrease in OPP in healthy participants using Doppler optical coherence tomography.MethodsFifteen healthy participants aged between 22 and 31 years (mean, 27 ± 3 years) were included in the present open study. IOP was increased stepwise via the suction cup method to induce a decrease in OPP. Retinal blood flow in arteries and veins was assessed using a custom-built Doppler optical coherence tomography system and pressure–flow relationships were calculated to assess autoregulation.ResultsSuction cup application induced a pronounced increase in IOP with a maximum value of 50.5 ± 8.0 mm Hg at the highest level of suction. Pressure–flow relationships revealed that blood flow was autoregulated until the OPP was decreased by approximately 21 mm Hg and started to decrease significantly when the OPP was reduced by 30 mm Hg. Retinal blood flow at the last suction period decreased at a maximum of –57.0 ± 22.3% and 65.2 ± 15.4% in retinal arteries and retinal veins, respectively. These changes in retinal blood flow were less pronounced than the decrease in OPP (–75.2 ± 19.2%), indicating retinal autoregulation.ConclusionsThe results of the present study confirm that retinal blood flow is autoregulated in response to changes in the OPP. Doppler optical coherence tomography has the potential to become a clinical tool for the investigation of retinal blood flow autoregulation in the future, because of its ability to assess the blood velocities and diameter of the retinal vessels parallel and therefore also their blood flow in absolute values. (Clinicaltrials.gov number NCT03398616)

Vascular Endothelial Glycocalyx as a Mechanism of Vascular Endothelial Dysfunction and Atherosclerosis

Atherosclerosis occurs as a result of organized processes that include vascular endothelial dysfunction, lipid accumulation, abnormal inflammatory reaction, excessive reactive oxygen species production, and vascular cell proliferation and migration. In patients with atherosclerosis, vascular endothelial dysfunction is commonly observed with the damage of vascular endothelial glycocalyx, which is an extracellular matrix bound to and encapsulating the endothelial cells that line the blood vessel wall. Unhealthy lifestyle choices such as smoking and physical inactivity also induce glycocalyx degradation. Additionally, vascular endothelial glycocalyx can be damaged by various pathological conditions including dehydration, acute infectious disease, trauma, sepsis, acute respiratory distress syndrome, Kawasaki disease, preeclampsia, gestational diabetes mellitus, hypertension, diabetes mellitus, chronic kidney disease, atherosclerosis, stroke, dementia, microvascular angina, acute coronary syndrome, and heart failure. Vascular endothelial glycocalyx has been shown to be important as a physical cytoprotective barrier for vascular endothelial cells and as a regulatory mechanism for intracellular cell signaling. Therefore, vascular endothelial glycocalyx has immense potential in the exploration of novel strategies for the evaluation of beneficial conditions of healthy vasculature.

(-)-Epicatechin protects thoracic aortic perivascular adipose tissue from whitening in high-fat fed mice.

High adipose tissue (AT) accumulation in the body increases the risk for many metabolic and chronic diseases. This work investigated the capacity of the flavonoid (-)-epicatechin to prevent undesirable modifications of AT in mice fed a high-fat diet. Studies were focused on thoracic aorta perivascular AT (taPVAT), which is involved in the control of blood vessel tone, among other functions. Male C57BL/6J mice were fed for 15 weeks a high-fat diet with or without added (-)-epicatechin (20 mg per kg body weight per d). In high-fat diet fed mice, (-)-epicatechin supplementation: (i) prevented the expansion of taPVAT, (ii) attenuated the whitening of taPVAT (according to the adipocyte morphology, diameter, and uncoupling-protein 1 (UCP-1) levels) and (iii) blunted the increase in plasma glucose and cholesterol. The observed taPVAT modifications were not associated with alterations in the aorta wall thickness, aorta tumor necrosis factor-alpha (TNF-α) and NADPH-oxidase 2 (NOX2) expression, and endothelial nitric oxide synthase (eNOS) phosphorylation levels. In summary, our results indicate (-)-epicatechin as a relevant bioactive protecting from the slow and silent development of metabolic and chronic diseases as they are associated with excessive fat intake.

Vitamin D as A Protector of Arterial Health: Potential Role in Peripheral Arterial Disease Formation.

Atherosclerotic occlusive diseases and aneurysms that affect large and medium-sized arteries outside the cardiac and cerebral circulation are collectively known as peripheral arterial disease (PAD). With a rise in the rate of aging population worldwide, the number of people diagnosed with PAD is rapidly increasing. The micronutrient vitamin D is an important steroid hormone that acts on many crucial cellular mechanisms. Experimental studies suggest that optimal levels of vitamin D have beneficial effects on the heart and blood vessels; however, high vitamin D concentrations have been implicated in promoting vascular calcification and arterial stiffness. Observations from various clinical studies shows that deficiency of vitamin D has been associated with a greater risk of PAD. Epidemiological studies have often reported an inverse relation between circulating vitamin D status measured in terms of 25-hydroxivitamin D [25(OH)D] levels and increased cardiovascular disease risk; however, randomized controlled trials did not show a consistent positive effect of vitamin D supplementation on cardiovascular disease risk or events. Even though PAD shares all the major risk factors with cardiovascular diseases, the effect of vitamin D deficiency in PAD is not clear. Current evidence suggests a strong role of vitamin D in promoting genomic and epigenomic changes. This review summarises the current literature that supports the notion that vitamin D deficiency may promote PAD formation. A better understanding of underlying pathological mechanisms will open up new therapeutic possibilities which is the main unmet need in PAD management. Furthermore, epigenetic evidence shows that a more holistic approach towards PAD prevention that incorporates a healthy lifestyle, adequate exercise and optimal nutrition may be more effective in protecting the genome and maintaining a healthy vasculature.

Resonances in the response of fluidic networks inherent to the cooperation between elasticity and bifurcations.

A global response function (GRF) of an elastic network is introduced as a generalization of the response function (RF) of a rigid network, relating the average flow along the network with the pressure difference at its extremes. The GRF can be used to explore the frequency behaviour of a fluid confined in a tree-like symmetric elastic network in which vessels bifurcate into identical vessels. We study such dynamic response for elastic vessel networks containing viscous fluids. We find that the bifurcation structure, inherent to tree-like networks, qualitatively changes the dynamic response of a single elastic vessel, and gives resonances at certain frequencies. This implies that the average flow throughout the network could be enhanced if the pulsatile forcing at the network’s inlet were imposed at the resonant frequencies. The resonant behaviour comes from the cooperation between the bifurcation structure and the elasticity of the network, since the GRF has no resonances either for a single elastic vessel or for a rigid network. We have found that resonances shift to high frequencies as the system becomes more rigid. We have studied two different symmetric tree-like network morphologies and found that, while many features are independent of network morphology, particular details of the response are morphology dependent. Our results could have applications to some biophysical networks, for which the morphology could be approximated to a tree-like symmetric structure and a constant pressure at the outlet. The GRF for these networks is a characteristic of the system fluid-network, being independent of the dynamic flow (or pressure) at the network’s inlet. It might therefore represent a good quantity to differentiate healthy vasculatures from those with a medical condition. Our results could also be experimentally relevant in the design of networks engraved in microdevices, since the limit of the rigid case is almost impossible to attain with the materials used in microfluidics and the condition of constant pressure at the outlet is often given by the atmospheric pressure.

Ring-array photoacoustic tomography for imaging human finger vasculature.

.For early diagnosis of rheumatoid arthritis (RA), it is important to visualize its potential marker, vascularization in the synovial membrane of the finger joints. Photoacoustic (PA) imaging, which can image blood vessels at high contrast and resolution, is expected to be a potential modality for earlier diagnosis of RA. In previous studies of PA finger imaging, different acoustic schemes, such as linear-shaped arrays, have been utilized, but these have limited detection views, rendering inaccurate reconstruction, and most of them require rotational detection. We are developing a PA system for finger vascular imaging using a ring-shaped array ultrasound (US) transducer. By designing the ring-array sensor based on simulations, using phantom experiments, it was demonstrated that we have created a system that can image small objects around 0.1 to 0.5 mm in diameter. The full width at half maximum of the slice direction of the system was within 2 mm and corresponded to that of the simulation. Moreover, we could clearly visualize healthy index finger vasculature and the location of the distal interphalangeal and proximal interphalangeal joints by PA and US echo images. In the future, this system could be used as a method for visualizing the three-dimensional vascularization of RA patients’ fingers.

Glioblastoma multiforme restructures the topological connectivity of cerebrovascular networks

Glioblastoma multiforme alters healthy tissue vasculature by inducing angiogenesis and vascular remodeling. To fully comprehend the structural and functional properties of the resulting vascular network, it needs to be studied collectively by considering both geometric and topological properties. Utilizing Single Plane Illumination Microscopy (SPIM), the detailed capillary structure in entire healthy and tumor-bearing mouse brains could be resolved in three dimensions. At the scale of the smallest capillaries, the entire vascular systems of bulk U87- and GL261-glioblastoma xenografts, their respective cores, and healthy brain hemispheres were modeled as complex networks and quantified with fundamental topological measures. All individual vessel segments were further quantified geometrically and modular clusters were uncovered and characterized as meta-networks, facilitating an analysis of large-scale connectivity. An inclusive comparison of large tissue sections revealed that geometric properties of individual vessels were altered in glioblastoma in a relatively subtle way, with high intra- and inter-tumor heterogeneity, compared to the impact on the vessel connectivity. A network topology analysis revealed a clear decomposition of large modular structures and hierarchical network organization, while preserving most fundamental topological classifications, in both tumor models with distinct growth patterns. These results augment our understanding of cerebrovascular networks and offer a topological assessment of glioma-induced vascular remodeling. The findings may help understand the emergence of hypoxia and necrosis, and prove valuable for therapeutic interventions such as radiation or antiangiogenic therapy.

Thymosin Β4 Mediates Vascular Protection Via Regulation Of Low Density Lipoprotein Receptor Related Protein 1 (Lrp1)

Abstract Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic switch which promotes atherosclerosis and susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesised that Thymosin β4 (Tβ4) may additionally function to maintain healthy vasculature and protect against disease throughout postnatal life. This was supported by identification of an interaction with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGF-BB signalling and VSMC proliferation. LRP1 variants have been identified by GWAS as major risk loci for AAA and coronary artery disease. Tβ4-null mice display aortic VSMC and elastin defects, phenocopying LRP1 mutants and suggesting compromised vascular integrity. We confirmed predisposition to disease in models of atherosclerosis and AAA. Diseased vessels and plaques were characterised by accelerated contractile-synthetic VSMC switching and augmented PDGFRβ signalling. In vitro, enhanced sensitivity to PDGF-BB, upon loss of Tβ4, coincided with dysregulated endocytosis, leading to increased recycling of LRP1-PDGFRβ and reduced lysosomal targeting. Our study identifies Tβ4 as a key regulator of LRP1 for maintaining vascular health, providing insight which may reveal useful therapeutic targets for modulation of VSMC phenotypic switching and disease progression.

Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing.

Cellular characteristics and their adjustment to a state of disease have become more evident due to recent advances in imaging, fluorescent reporter mice, and whole genome RNA sequencing. The uncovered cellular heterogeneity and/or plasticity potentially complicates experimental studies and clinical applications, as markers derived from whole tissue ‘bulk’ sequencing is unable to yield a subtype transcriptome and specific markers. Here, we propose definitions on heterogeneity and plasticity, discuss current knowledge thereof in the vasculature and how this may be improved by single-cell sequencing (SCS). SCS is emerging as an emerging technique, enabling researchers to investigate different cell populations in more depth than ever before. Cell selection methods, e.g. flow assisted cell sorting, and the quantity of cells can influence the choice of SCS method. Smart-Seq2 offers sequencing of the complete mRNA molecule on a low quantity of cells, while Drop-seq is possible on large numbers of cells on a more superficial level. SCS has given more insight in heterogeneity in healthy vasculature, where it revealed that zonation is crucial in gene expression profiles among the anatomical axis. In diseased vasculature, this heterogeneity seems even more prominent with discovery of new immune subsets in atherosclerosis as proof. Vascular smooth muscle cells and mesenchymal cells also share these plastic characteristics with the ability to up-regulate markers linked to stem cells, such as Sca-1 or CD34. Current SCS studies show some limitations to the number of replicates, quantity of cells used, or the loss of spatial information. Bioinformatical tools could give some more insight in current datasets, making use of pseudo-time analysis or RNA velocity to investigate cell differentiation or polarization. In this review, we discuss the use of SCS in unravelling heterogeneity in the vasculature, its current limitations and promising future applications.

1933-P: Acute Hyperglycemia + Hyperinsulinemia Increases Carotid-Femoral Arterial Stiffness and Perfusion of Skeletal Muscle in Healthy Subjects

Introduction: Chronic hyperglycemia injures both micro-and microvasculature. Conversely, insulin stimulates vascular nitric oxide production and acts as a vasodilator. Whether acute hyperglycemia (AH) inhibits insulin’s vasodilator action in healthy vasculature is unknown. Here we tested whether AH interfered with insulin’s action to recruit microvasculature, enhance endothelial function, or diminish vascular stiffness. Methods: Nine healthy, fasting subjects (ages 18-35 years; BMI 18-25 kg/m2) twice received a 1 mU/kg/minute 2-hour insulin clamp. On one occasion, subjects were euglycemic (EH); and on the second, were hyperglycemic (∼200 mg/dL) (HH) for 2 hours before and throughout the clamp. Octreotide infusion blocked endogenous insulin in both studies. We assessed endothelial function by flow-mediated dilation (FMD) and arterial stiffness with pulse wave velocity (PWV) and augmentation index (AI). We used contrast-enhanced ultrasound to measure insulin-mediated capillary recruitment in skeletal and cardiac muscle. Linear mixed model was used for statistical analysis, with Bonferroni correction for comparison between studies. Results: Insulin increased carotid-femoral PWV (p=0.02 for Δ PWV) but decreased AI (p= 0.02) during HH, with AI significantly reduced in HH compared to EH (p=0.04). Insulin recruited microvasculature (p<0.05) with either EH or HH, and microvascular blood volume (p=0.03) and blood flow (p=0.04) significantly increased in skeletal muscle after HH. No changes were observed in FMD or cardiac microvascular perfusion with either condition. Discussion: This study provides evidence that 4 hours of AH evokes insulin-induced increases of carotid-femoral arterial stiffness in healthy subjects. Insulin’s ability to recruit microvasculature is preserved during AH. Disclosure W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: Research Support; Self; AstraZeneca. Funding National Institutes of Health (F32HL142304-01)

Dietary Glycocalyx Precursor Supplementation Ameliorates Age‐Related Vascular Dysfunction

Large elastic artery stiffening and endothelial dysfunction, and associated reductions in nitric oxide (NO) bioavailability, are central features of vascular aging. We have recently demonstrated that the glycocalyx, a gel‐like structure that is bound to the luminal surface of the vascular endothelium, is dysfunctional in the aged vasculature. The glycocalyx has several functions that are critical for the maintenance of a healthy vasculature. We sought to determine if chronic dietary supplementation of glycocalyx precursors (glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan) could restore glycocalyx function, while concomitantly ameliorating age‐related vascular dysfunction. Young (Y: 7 mo) and old (O: 30 mo) male B6D2F1 mice consumed a control (C) or glycocalyx precursor (GP: 37 mg/kg encapsulated chow provided courtesy of MicroVascular Health Solutions, LLC [U.S. Patent Serial No. 9,943,572]) diet ad libitum for 10 weeks. Glycocalyx barrier function (perfused boundary region [PBR]) was evaluated in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. PBR was ~13% higher in OC compared to YC, suggestive of an age‐related impairment in glycocalyx barrier function, and this was normalized in OGP mice (Both P<0.05; Figure 1). At baseline, aortic pulse wave velocity (PWV), a measure of large artery stiffness, was higher in OC and OGP compared with YC mice (Both P<0.05; Figure 2). However, after the dietary intervention, PWV decreased by ~13% in OGP (P<0.05), whereas, PWV was unchanged in OC and YC mice after the 10 week period (P>0.05). We assessed endothelial function by endothelium‐dependent dilation (EDD, maximal response to acetylcholine [ACh]) in the carotid artery. Carotid artery EDD was higher in YC and OGP compared to OC mice (92.5±2.4 and 90.7±2.3 vs. 69.0±4.9%, respectively, P<0.05). EDD of OGP was similar to YC mice (P>0.05). After incubation with the nitric oxide (NO) synthase inhibitor, L‐NAME, the dilatory response did not differ between groups (P>0.05). NO bioavailability (max ACh dilation ‐ max ACh+L‐NAME dilation) was ~10–14 fold higher in YC and OGP compared to OC mice (Both P<0.05; Figure 3). Endothelium‐independent dilation (vasodilation to sodium nitroprusside) was not different between groups (P>0.05). In young mice, GP diet did not affect any of the aforementioned measurements (P>0.05). In conclusion, 10 weeks of dietary GP supplementation in old mice restores glycocalyx barrier function that is accompanied by reduced aortic stiffness and augmented EDD and NO bioavailability, suggesting that the glycocalyx may be an effective therapeutic target for vascular dysfunction in older adults.Support or Funding InformationThis study was funded in part by grants from the National Institute of Health (R01 AG040297, R01 AG048366, K02 AG045339, K99 AT010017) and US Department of Veterans Affairs (1I01BX002151).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Paying the Toll for Inflammation

Paying the Toll for Inflammation

Elevated Vascular Endothelial Growth Factor Level in Association with Mean Platelet Volume Are Emerging Risk Factors for Vascular Complications in T2DM Patients

Increasing evidence in both experimental and clinical studies suggests oxidative stress (OS) plays a major role in the pathogenesis of type 2 diabetes mellitus and its complications. In a physiological condition, appropriate levels of ROS, generated either in restricted amounts or transient fashion, are required to promote physiological angiogenesis and homeostatic maintenance of healthy vasculature. Uncontrolled continuous ROS production will ultimately contribute to pathology and cause tissue damage. One of the most important proangiogenic factors is vascular endothelial growth factor (VEGF) which plays a key role in diabetic endothelial dysfunction, which ultimately leads to pathogenesis of vascular complications. As VEGF is released by activated platelets, hence platelet activation could be the source of VEGF in plasma samples. Increased platelet activity is emphasized to play a role in the development of vascular complications in T2DM patients and platelet volume, a marker of the platelet function and activation, is measured as mean platelet volume (MPV). Therefore, we aimed to investigate the association between plasma VEGF levels and MPV levels that may lead to vascular complications. A case-control study of one hundred patients with T2DM (n = 100) and thirty control subjects (n = 30) were screened from different areas of West Bengal. All procedures were done with the informed consent of participants. Elevated VEGF level was found in T2DM patients (526.8 ± 34.3 pg/ml) compared to healthy controls (317.9 ± 12.9 pg/ml) which was statistically significant. T2DM patients had higher MPV (12.5 ± 0.2 fl) compared to controls (11.4 ± 0.2 fl). Thus the present study showed a significant association between VEGF level in plasma and MPV indicating the severity of vascular complications. Hence, in conclusion, it suggested that VEGF levels along with MPV are a reliable biomarker for evaluating the development and progression of vascular complications.

Meet the First Authors.

Meet the First Authors.

The role of placental growth factor (PlGF) and its receptor system in retinal vascular diseases.

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. Upon binding to VEGF- and neuropilin-receptor sub-types, PlGF modulates a range of neural, glial and vascular cell responses that are distinct from VEGF-A. As PlGF expression is selectively associated with pathological angiogenesis and inflammation, its blockade does not affect the healthy vasculature. PlGF actions have been extensively described in tumor biology but more recently there has been accumulating preclinical evidence that indicates that this growth factor could have an important role in retinal diseases. High levels of PlGF have been found in aqueous humor, vitreous and/or retina of patients exhibiting retinopathies, especially those with diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD). Expression of this growth factor seems to correlate closely with many of the key pathogenic features of early and late retinopathy in preclinical models. For example, studies using genetic modification and/or pharmacological treatment to block PlGF in the laser-induced choroidal neovascularization (CNV) model, oxygen-induced retinopathy model, as well as various murine diabetic models, have shown that PlGF deletion or inhibition can reduce neovascularization, retinal leakage, inflammation and gliosis, without affecting vascular development or inducing neuronal degeneration. Moreover, an inhibitory effect of PlGF blockade on retinal scarring in the mouse CNV model has also been recently demonstrated and was found to be unique for PlGF inhibition, as compared to various VEGF inhibition strategies. Together, these preclinical results suggest that anti-PlGF therapy might have advantages over anti-VEGF treatment, and that it may have clinical applications as a standalone treatment or in combination with anti-VEGF. Additional clinical studies are clearly needed to further elucidate the role of PlGF and its potential as a therapeutic target in ocular diseases.

Distinct Retinal Capillary Plexuses in Normal Eyes as Observed in Optical Coherence Tomography Angiography Axial Profile Analysis

Optical coherence tomography angiography (OCTA) allows the retinal microvasculature to be visualized at various retinal depths. Previous studies introduced OCTA axial profile analysis and showed regional variations in the number and location of axially distinct vascular retinal plexuses. OCTA acquisition and processing approaches, however, vary in terms of their resulting transverse and axial resolutions, and especially the latter could potentially influence the profile analysis results. Our study imaged normal eyes using the Spectralis OCT2 with a full-spectrum, probabilistic OCTA algorithm, that, in marked contrast to split-spectrum approaches, preserves the original high OCT axial resolution also within the resulting OCTA signal. En face OCTA images are generally created by averaging flow signals over a finite axial depth window. However, we assessed regional OCTA signal profiles at each depth position at full axial resolution. All regions had two sharp vessel density peaks near the inner and outer boundaries of the inner nuclear layer, indicating separate intermediate and deep capillary plexuses. The superficial vascular plexus (SVP) separated into two distinct peaks within the ganglion cell layer in the parafoveal zone. The nasal, superior, and inferior perifovea had a deeper SVP peak that was shifted anteriorly compared to the parafoveal zone. Axial vascular density analysis with high-resolution, full spectrum OCTA thus allows healthy retinal vasculature to be precisely reconstructed and may be useful for clinically assessing retinal pathology.

Activation of Endogenous Piezo1 Channels by Shear Stress in Excised Membrane Patches

The sensing of shear stress arising because of blood flow is critical in vascular development and maintenance of a healthy vasculature in the adult. The identity of molecules which sense and transduce this force into appropriate vascular anatomy and function is therefore keenly sought. A central question is whether there is a force sensor protein (“receptor”) which directly detects the force, acting either alone or in complex with other proteins. Piezo1 channels are Ca2+-permeable non-selective cationic channels which are activated by membrane stretch. These channels are important for shear stress-sensing and vascular function in embryonic and adult mice (Li et al 2014 Nature 515, 279-; Rode et al 2017 Nature Communications 8, 350-). We have used patch-clamp recording to study the channels in freshly isolated endothelium of second-order mesenteric arteries of adult mice. The pipette solution contained (mM): 145 KCl, 1 MgCl2, 0.5 EGTA, 10 HEPES. Whole-cell perforated patch recordings from endothelial fragments revealed a resting membrane potential of −43 mV which was depolarized by fluid flow. When Piezo1 was conditionally deleted in endothelium the resting potential was hyperpolarized and fluid flow-evoked depolarization was absent (Rode et al 2017). Outside-out patches were then excised from endothelium and found to contain constitutive single channel activity with the expected 25-pS unitary conductance of Piezo1 channels; the channel activity could be further enhanced by fluid flow and inhibited by the non-selective Piezo1 channel inhibitor, Gd3+, and was absent in Piezo1 knockout mice (Rode et al 2017). The data suggest Piezo1 channels of the endothelium can be activated by shear stress in a sparse excised membrane environment, consistent with direct sensing of shear stress or a closely-associated force. The research was supported by grants from the British Heart Foundation, MRC, Wellcome Trust.

Investigating the effects of a penetrating vessel occlusion with a multi-scale microvasculature model of the human cerebral cortex

The effect of the microvasculature on observed clinical parameters, such as cerebral blood flow, is poorly understood. This is partly due to the gap between the vessels that can be individually imaged in humans and the microvasculature, meaning that mathematical models are required to understand the role of the microvasculature. As a result, a multi-scale model based on morphological data was developed here that is able to model large regions of the human microvasculature. From this model, a clear layering of flow (and 1-dimensional depth profiles) was observed within a voxel, with the flow in the microvasculature being driven predominantly by the geometry of the penetrating vessels. It also appears that the pressure and flow are decoupled, both in healthy vasculatures and in those where occlusions have occurred, again due to the topology of the penetrating vessels shunting flow between them. Occlusion of a penetrating arteriole resulted in a very high degree of overlap of blood pressure drop with experimentally observed cell death. However, drops in blood flow were far more widespread, providing additional support for the theory that pericyte controlled regulation on the capillary scale likely plays a large part in the perfusion of tissue post-occlusion.

Pathogenic role of ion channels in pulmonary arterial hypertension.

Pathogenic role of ion channels in pulmonary arterial hypertension.

Engineering cell aggregates through incorporated polymeric microparticles

Cell-scaled polymer microparticles (MPs) integrated into cellular aggregates have been shown to be a powerful tool to direct cell response. MPs have supported the development of healthy cartilage, islets, nerves, and vasculature by the maintenance of soluble gradients as well as by the local presentation of tethered cues and diffusing proteins and small molecules. MPs integrated with pluripotent stem cells have directed in vivo expansion and differentiation. Looking forward, MPs are expected to support both the characterization and development of in vitro tissue systems for applications such as drug testing platforms. However, useful co-cultures must be designed keeping in mind the limitations and attributes of each material strategy within the context of the overall tissue biology. The present review integrates prospectives from materials development, drug delivery, and tissue engineering to provide a toolbox for the development and application of MPs useful for long-term co-culture within cell aggregates.