Flow correlated percolation during vascular network formation in tumors

A theoretical model based on the molecular interactions between a growing tumor and a dynamically evolving blood vessel network describes the transformation of the regular vasculature in normal tissues into a highly inhomogeneous tumor specific capillary network. The emerging morphology, characterized by the compartmentalization of the tumor into several regions differing in vessel density, diameter and necrosis, is in accordance with experimental data for human melanoma. Vessel collapse due to a combination of severely reduced blood flow and solid stress exerted by the tumor, leads to a correlated percolation process that is driven towards criticality by the mechanism of hydrodynamic vessel stabilization.Comment: 4 pages, 3 figures (higher resolution at http://www.uni-saarland.de/fak7/rieger/HOMEPAGE/flow.eps

Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, image-guided biopsies, and quantitative immunohistochemistry.

To evaluate the association between a vessel size index (VSIMRI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSIMRI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSIMRI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSIMRI = 13.67 μm and VSIHistology = 12.60 μm, with slight overestimation of VSIMRI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSIMRI and VSIHistology (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber

PENGARUH BEVACIZUMAB TERHADAP ANGIOGENESIS PADA AREA TRABEKULEKTOMI (Studi Eksperimental pada Oryctolagus Cuniculus)

Objective : to examine the effect of Bevacizumab injection to the angiogenesis which the amount and density of blood vessel as the indicators after trabeculectomy procedure. Method : This was a true experimental study using 16 eyes of 16 New Zealand White Rabbit eye treated by trabeculectomy procedure with eight eyes as the control group using Balanced Saline Solution (BSS) and eight eyes as the treatment group using Bevacizumab. It was injected subconjuctiva after the trabeculectomy. At the end of the study all rabbits in each group was sacrified, the eye was enucleated and the bleb area was dissected, and then processed for histological studies. The amount and density of blood vessel were evaluated using haematoxyllin eosin methode at day 14 after the eyes was done for trabeculectomy procedure. Result : The mean of amount of blood vessel in control group was 22,63 ± 11,02 and treatment group was 14,75 ± 4,92 (p=0.043). The mean of density of blood vessel in control group was 19,10 ± 1,69 % and treatment group was 16,53 ± 2,90 % (p=0.029)%. The result shows there were statistically significant difference between the two groups (p<0.05). Conclusion : In this study the subconjunctival Bevacizumab injection after trabeculectomy reduce the amount and density of blood vessel compared with subconjunctival BSS injection only, thus it is potential in preventing subconjunctival fibrosis after trabeculectomy

Flow-correlated dilution of a regular network leads to a percolating network during tumor induced angiogenesis

We study a simplified stochastic model for the vascularization of a growing tumor, incorporating the formation of new blood vessels at the tumor periphery as well as their regression in the tumor center. The resulting morphology of the tumor vasculature differs drastically from the original one. We demonstrate that the probabilistic vessel collapse has to be correlated with the blood shear force in order to yield percolating network structures. The resulting tumor vasculature displays fractal properties. Fractal dimension, microvascular density (MVD), blood flow and shear force has been computed for a wide range of parameters.Comment: 15 pages, 12 figure

Vasculature of the paraventricular nucleus of the hypothalamus: influence of development, gamma-aminobutyric acid (GABA) receptors, and prenatal glucocorticoids, The

2014 Spring.The paraventricular nucleus of the hypothalamus (PVN) is a critical brain region that regulates many homeostatic and stress responses. In addition to its dense cytoarchitecture, it also contains a vast network of blood vessels. These blood vessels within the mouse PVN have a higher density than other brain regions, which develops postnatally. Loss of gamma aminobutyric acid (GABA) signaling or prenatal dexamethasone (dex) treatment decreased the blood vessel density. Dex also decreased blood brain barrier (BBB) competency while increasing desmin-immunoreactive pericytes at postnatal day (P)20. Long-term consequences included a decrease in GFAP contact with blood vessels selectively in dex-treated females, and an increase in depression-like behaviors in dex-treated males. Chapter 2 examines the blood vessel density within the PVN. Initially the blood vessel density is similar than surrounding brain regions, then after P8 there was an increase that resulted in a highly vascularized network around P20. The highest densities were restricted to the rostral and mid regions of the PVN, where the neuroendocrine neurons are housed. In addition, mice lacking a functional GABAB receptor had a significant decrease in blood vessel density in the mid region at P20. The protein endocan has been proposed to be a "tip cell" marker, indicating angiogenesis. To further characterize the postnatal angiogenic period within the PVN, recently developed antibodies against endocan were used. Chapter 3 provides evidence that endocan is normally expressed in the mouse brain but not restricted to tip cells. In addition, prior perfusion with fluorescein isothiocyanate (FITC) prevents endocan-immunoreactivity (ir) and provides a novel method for identifying non-functional blood vessels. Chapters 4 and 5 show that excess fetal glucocorticoids alters the BBB within the PVN at two time points. At P20, there was a loss of BBB integrity accompanied by an increase in desmin-ir pericytes on a reduced blood vessel network due to dex-treatment for both prepubertal males and females. In contrast at P50, the blood vessel density and BBB were no longer disrupted following fetal dex-treatment. However, there was a decrease in glial fibrillary acidic protein (GFAP)-ir astrocytes in dex-treated females and an increase in desmin-ir pericytes in dextreated males. In conclusion, the work set forth in this dissertation indicates that the dense vascular network within the PVN develops postnatally and is susceptible to regulation by both exogenous and endogenous factors

Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma

The aims of this study were to investigate the role of vascular invasion (blood and lymphatic), vessel density and the presence of tumour-associated macrophages as prognostic markers in 202 cutaneous melanoma patients. Sections of primary melanoma were stained with lymphatic-specific antibody D2-40 to assess lymphatic vessel invasion and density in intratumoural and peritumoural areas; an antibody against endothelial marker CD34 was used to determine blood vessel invasion and density, and an antibody against CD68 was used to determine macrophage counts. Immunohistochemically determined vascular invasion (combined blood and lymphatic) was compared with that determined using haematoxylin and eosin (H&E) staining. The use of immunohistochemistry increased detection of vascular invasion from 8–30% of patients, and histological exam of H&E-stained tissue was associated with a false positive rate of 64%. Lymphatic vessel invasion occurred at a much higher frequency than blood vessel invasion (27 and 4% of patients, respectively). Although immunohistochemically detected vessel invasion was significantly associated with histological markers of adverse prognosis, such as increased Breslow thickness, ulceration and mitotic rate (all P<0.001), no associations with relapse-free or overall survival were observed. High macrophage counts were significantly associated with markers of aggressive disease, such as Breslow thickness, ulceration and mitotic rate (P<0.001, P<0.001, P=0.005, respectively), and lymphatic vessel invasion and high microvessel density (P=0.002 and P=0.003, respectively). These results suggest that vascular invasion is more accurately detected using immunohistochemistry and occurs predominantly via lymphatic vessels. The association of vessel characteristics with histological characteristics of the primary melanoma provides evidence for their biological importance in melanoma, but that they were not associated with clinical outcome attests to the value of existing histological prognostic biomarkers. We note that a high macrophage count may be associated with neovascularisation and primary tumour growth, and may also promote invasion through lymphatic vessels

A multiphase model describing vascular tumour growth

In this paper we present a new model framework for studying vascular tumour growth, in which the blood vessel density is explicitly considered. Our continuum model comprises conservation of mass and momentum equations for the volume fractions of tumour cells, extracellular material and blood vessels. We include the physical mechanisms that we believe to be dominant, namely birth and death of tumour cells, supply and removal of extracellular fluid via the blood and lymph drainage vessels, angiogenesis and blood vessel occlusion. We suppose that the tumour cells move in order to relieve the increase in mechanical stress caused by their proliferation. We show how to reduce the model to a system of coupled partial differential equations for the volume fraction of tumour cells and blood vessels and the phase averaged velocity of the mixture. We consider possible parameter regimes of the resulting model. We solve the equations numerically in these cases, and discuss the resulting behaviour. The model is able to reproduce tumour structure that is found `in vivo' in certain cases. Our framework can be easily modified to incorporate the effect of other phases, or to include the effect of drugs

Characterization of Laser-Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy.

Background and objectivesPort wine stain (PWS) is a congenital vascular malformation of the human skin. Laser is the treatment of choice for PWS. Laser-resistant PWS is one crucial factor accounting for inadequate treatment outcome, which needs to be fully characterized. This study aims to quantitatively characterize the morphology of laser-resistant PWS blood vessels in the upper papillary dermis using in vivo reflectance confocal microscopy (RCM).Study design/materials and methodsA total of 42 PWS subjects receiving laser treatment from August 2016 through July 2018 were enrolled into this study. Thirty-three subjects had facial PWS; nine had extremity PWS. All subject's PWS received multiplex 585/1,064 nm laser treatment. RCM images were taken before and after treatment. The density, diameter, blood flow, and depth of PWS blood vessels were analyzed.ResultsWe found 44.4% PWS on the extremities (four out of nine subjects) were laser-resistant, which was significantly higher (P &lt; 0.001) when compared with those PWS on the face (15.2%, 5 out of 33 subjects). The laser-resistant facial PWS blood vessels had significantly higher blood flow (1.35 ± 0.26 U vs. 0.89 ± 0.22 U, P &lt; 0.001), larger blood vessel diameters (109.60 ± 18.24 µm vs. 84.36 ± 24.04 µm, P = 0.033) and were located deeper in the skin (106.01 ± 13.87 µm vs. 87.82 ± 12.57 µm, P &lt; 0.001) in the skin when compared with laser-responsive PWS on the face. The average PWS blood vessel density (17.01 ± 4.63/mm2 vs. 16.61 ± 4.44/mm2 , P = 0.857) was not correlated to the laser resistance.ConclusionsLaser-resistant PWS blood vessels had significantly higher blood flow, larger diameters, and were located deeper in the skin. RCM can be a valuable tool for a prognostic evaluation on laser-resistant lesions before treatment, thereby providing guidance for tailored laser treatment protocols, which may improve the therapeutic outcome. The limitations for this study include relative small sample size and acquisitions of different blood vessels before and after 2 months of treatment. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc

Supervised machine learning based multi-task artificial intelligence classification of retinopathies

Artificial intelligence (AI) classification holds promise as a novel and affordable screening tool for clinical management of ocular diseases. Rural and underserved areas, which suffer from lack of access to experienced ophthalmologists may particularly benefit from this technology. Quantitative optical coherence tomography angiography (OCTA) imaging provides excellent capability to identify subtle vascular distortions, which are useful for classifying retinovascular diseases. However, application of AI for differentiation and classification of multiple eye diseases is not yet established. In this study, we demonstrate supervised machine learning based multi-task OCTA classification. We sought 1) to differentiate normal from diseased ocular conditions, 2) to differentiate different ocular disease conditions from each other, and 3) to stage the severity of each ocular condition. Quantitative OCTA features, including blood vessel tortuosity (BVT), blood vascular caliber (BVC), vessel perimeter index (VPI), blood vessel density (BVD), foveal avascular zone (FAZ) area (FAZ-A), and FAZ contour irregularity (FAZ-CI) were fully automatically extracted from the OCTA images. A stepwise backward elimination approach was employed to identify sensitive OCTA features and optimal-feature-combinations for the multi-task classification. For proof-of-concept demonstration, diabetic retinopathy (DR) and sickle cell retinopathy (SCR) were used to validate the supervised machine leaning classifier. The presented AI classification methodology is applicable and can be readily extended to other ocular diseases, holding promise to enable a mass-screening platform for clinical deployment and telemedicine.Comment: Supplemental material attached at the en

Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment

Abstract Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood–brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell—endothelial cell signalling leading to blood–brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood–brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood–brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood–brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood–brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood–brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease