scholarly journals Intravital microscopy of tumor vessel morphology and function using a standard fluorescence microscope

2021 ◽  
Author(s):  
Jon-Vidar Gaustad ◽  
Trude G. Simonsen ◽  
Lise Mari K. Hansem ◽  
Einar K. Rofstad
Keyword(s):  
Blood Supply ◽  
Intravital Microscopy ◽  
Small Diameter ◽  
Fluorescence Microscope ◽  
Tumor Vessel ◽  
Antiangiogenic Treatment ◽  
Fluorescent Marker ◽  
Vascular Morphology ◽  
Vessel Morphology ◽  
And Function

Abstract Purpose The purpose of the study was to demonstrate the performance and possible applications of an intravital microscopy assay using a standard fluorescence microscope. Methods Melanoma and pancreatic ductal adenocarcinoma xenografts were initiated in dorsal window chambers and subjected to repeated intravital microscopy. The entire tumor vasculature as well as the normal tissue surrounding the tumor was imaged simultaneously with high spatial and temporal resolution. Vascular morphology images were recorded by using transillumination, and vascular masks were produced to quantify vessel density, vessel diameter, vessel segment length, and vessel tortuosity. First-pass imaging movies were recorded after an intravenous injection of a fluorescent marker and were used to investigate vascular function. Lymphatics were visualized by intradermal injections of a fluorescent marker. Results The intravital microscopy assay was used to study tumor growth and vascularization, tumor vessel morphology and function, tumor-associated lymphatics, and vascular effects of acute cyclic hypoxia and antiangiogenic treatment. The assay was sensitive to tumor-line differences in vascular morphology and function and detected tumor-induced lymphatic dilation. Acute cyclic hypoxia induced angiogenesis and increased the density of small diameter vessels and blood supply times, whereas antiangiogenic treatment selectively removed small-diameter vessels, reduced blood supply times, and induced hypoxia. Moreover, the window chamber was compatible with magnetic resonance imaging (MRI), and parametric images derived by dynamic contrast-enhanced MRI were shown to reflect vascular morphology and function. Conclusions The presented assay represents a useful and affordable alternative to intravital microscopy assays using confocal and multi-photon microscopes.

scholarly journals Edema Control by Cediranib, a Vascular Endothelial Growth Factor Receptor–Targeted Kinase Inhibitor, Prolongs Survival Despite Persistent Brain Tumor Growth in Mice

2009 ◽  
Vol 27 (15) ◽  
pp. 2542-2552 ◽  
Author(s):  
Walid S. Kamoun ◽  
Carsten D. Ley ◽  
Christian T. Farrar ◽  
Annique M. Duyverman ◽  
Johanna Lahdenranta ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Intravital Microscopy ◽  
Kinase Inhibitor ◽  
Molecular Techniques ◽  
Antitumor Effects ◽  
Vascular Morphology ◽  
Anti Vegf ◽  
And Function ◽  
Endothelial Growth Factor

Purpose Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. Methods We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers. Results We show by intravital microscopy that cediranib significantly decreased tumor vessel permeability and diameter. Moreover, cediranib treatment induced normalization of perivascular cell coverage and thinning of the basement membrane, as mirrored by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation—as measured by MRI and by dry/wet weight measurement of water content—but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage infiltration and significant but minor changes in tumor cell proliferation and apoptosis. Systemically, cediranib increased plasma VEGF and placenta growth factor levels, and the number of circulating CXCR4+CD45+ cells. However, by controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth. Conclusion Anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth.

scholarly journals NG2 expression regulates vascular morphology and function in human brain tumours

NeuroImage ◽  
2006 ◽  
Vol 29 (3) ◽  
pp. 965-976 ◽  
Author(s):  
C. Brekke ◽  
A. Lundervold ◽  
P.Ø. Enger ◽  
C. Brekken ◽  
E. Stålsett ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tumours ◽  
Vascular Morphology ◽  
Human Brain Tumours ◽  
And Function

scholarly journals Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies

2019 ◽  
Vol 116 (7) ◽  
pp. 2662-2671 ◽  
Author(s):  
Chrysovalantis Voutouri ◽  
Nathaniel D. Kirkpatrick ◽  
Euiheon Chung ◽  
Fotios Mpekris ◽  
James W. Baish ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Tumor Evolution ◽  
Combination Therapies ◽  
Tumor Vessel ◽  
Antiangiogenic Treatment ◽  
Antiangiogenic Drugs ◽  
Underlying Mechanisms ◽  
Computational Analyses

Cooption of the host vasculature is a strategy that some cancers use to sustain tumor progression without—or before—angiogenesis or in response to antiangiogenic therapy. Facilitated by certain growth factors, cooption can mediate tumor infiltration and confer resistance to antiangiogenic drugs. Unfortunately, this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood. Here, we analyzed the dynamics of vessel cooption during tumor progression and in response to antiangiogenic treatment in gliomas and brain metastases. We followed tumor evolution during escape from antiangiogenic treatment as cancer cells coopted, and apparently mechanically compressed, host vessels. To gain deeper understanding, we developed a mathematical model, which incorporated compression of coopted vessels, resulting in hypoxia and formation of new vessels by angiogenesis. Even if antiangiogenic therapy can block such secondary angiogenesis, the tumor can sustain itself by coopting existing vessels. Hence, tumor progression can only be stopped by combination therapies that judiciously block both angiogenesis and cooption. Furthermore, the model suggests that sequential blockade is likely to be more beneficial than simultaneous blockade.

Structure and function in the excretory system of archaeogastropods and their significance in the evolution of gastropods

1985 ◽  
Vol 310 (1145) ◽  
pp. 383-406 ◽  
Keyword(s):  
Blood Supply ◽  
Renal Vein ◽  
Left Kidney ◽  
Structure And Function ◽  
Excretory System ◽  
Ultrastructural Organization ◽  
Primary Role ◽  
Partial Restoration ◽  
The Right ◽  
And Function

Three species of archaeogastropod mollusc, Monodonta lineata (da Costa), Emarginula reticulata Sowerby and Patella vulgata L. were selected as representative members of the Trochacea, Fissurellacea and Patellacea, respectively, for a comparative anatomical and ultrastructural study of the excretory system. Primary urine formation takes place by filtration of blood through the walls of the paired auricles in Monodonta and Emarginula and of the single auricle and ventricle in Patella . Urine then passes to right and left kidneys along the renopericardial canals. Contrary to earlier reports the two kidneys are different in structure and function in all three species, the larger right kidney retaining the primitive function of nitrogenous excretion, the left having a predominantly resorptive role and with a capacity to abstract from the blood solutes of larger molecular mass. The difference in the size of the two kidneys is exaggerated in Patella and Emarginula as a consequence of partial restoration of bilateral symmetry in these limpets. It has been possible to demonstrate at the ultrastructural level that the minute left kidney of Emarginula is functional. The vacuolated epithelial cells of the right kidney contain layered excretory spherules composed of purines, melanin and ferric iron in different proportions in the three genera. There is close similarity in the ultrastructural organization of these cells in Monodonta and Emarginula , but those of Patella show marked differences and their excretory spherules contain a higher proportion of melanin. The position of the left kidney in the mantle skirt, as exemplified by Monodonta , is believed to have arisen in the earliest gastropods correlated with the development of helical coiling. This was accompanied by a change in its blood vessels. It has lost its afferent renal vein, which primitively would have carried deoxygenated blood from the viscera, an arrangement which persists in the right kidney. The left efferent renal vein is reduced in Monodonta and lost in Patella and Emarginula . A new vessel has arisen linking left auricle and left kidney and there is evidence to suggest that it carries post-branchial oxygenated blood. It is believed to serve as both an afferent and major efferent route. The physiological implications of this change in the blood supply are discussed and held to be responsible for the functional differences between the two kidneys, creating conditions in the left which favour resorption of organic solutes and ions, and leaving the right kidney with the primary role of nitrogenous excretion. The evolution of the nephridial gland is examined in this context and is also believed to be correlated with the change in the blood supply to the left kidney. Ultrastructural evidence is given in support of its suggested resorptive function. The significance of the differences between right and left kidneys of archaeogastropods is discussed in relation to the evolution of the monotocardian excretory system, and the possible phylogenetic relationships of the groups of archaeogastropods are considered.

Marriage of resistance and conduit arteries breeds critical limb ischemia

2005 ◽  
Vol 288 (3) ◽  
pp. H1044-H1050 ◽  
Author(s):  
Paul Coats ◽  
Roger Wadsworth
Keyword(s):  
Blood Supply ◽  
Critical Limb Ischemia ◽  
Limb Ischemia ◽  
Sudden Increase ◽  
Large Artery ◽  
Resistance Arteries ◽  
Tissue Edema ◽  
Surgical Bypass ◽  
Small Resistance ◽  
And Function

Atherosclerosis in a major leg artery leads to impaired blood supply, which normally progresses to critical limb ischemia. Atherosclerosis produces substantial alterations of structure and endothelial function in the large conduit arteries. Pressure unloading and ischemia in the distal vasculature bring about alterations in microvascular function. Resistance arteries undergo significant wall thinning and changes in their contractile regulation. Optimization of large artery dimensions by the small arteries through flow-mediated vasodilation is impaired. Angiogenesis is stimulated, which can result in the formation of major collateral feeder vessels in addition to small nutritive blood vessels. However, angiogenesis can also contribute to instability of atherosclerotic plaques, which ultimately leads to further deterioration in blood supply. Surgical bypass grafting to restore blood supply to the distal leg generates a sudden increase of pressure in the weakened resistance vasculature, leading to uncontrolled changes in capillary hydrostatic pressure, extravasation of fluid, and tissue edema. This review aims to highlight the importance of the resistance vasculature in critical limb ischemia and the interdependence of pathophysiological changes in the large conduit and small resistance arteries. The major unresolved question is why the physiological mechanisms that regulate vascular structure and function ultimately break down, leading to circulatory failure within the distal limb.

Vascular dysfunction in S1P2 sphingosine 1-phosphate receptor knockout mice

2007 ◽  
Vol 292 (1) ◽  
pp. R440-R446 ◽  
Author(s):  
John N. Lorenz ◽  
Lois J. Arend ◽  
Rachel Robitz ◽  
Richard J. Paul ◽  
A. John MacLennan
Keyword(s):  
Knockout Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Morphology ◽  
Relative Contribution ◽  
Sphingosine 1 Phosphate ◽  
In Vivo Analysis ◽  
And Function ◽  
Isometric Forces

There is growing evidence that sphingosine 1-phosphate (S1P) plays an important role in regulating the development, morphology, and function of the cardiovascular system. There is little data, however, regarding the relative contribution of endogenous S1P and its cognate receptors (referred to as S1P1–5) to cardiovascular homeostasis. We used S1P2 receptor knockout mice (S1P2−/−) to evaluate the role of S1P2 in heart and vascular function. There were no significant differences in blood pressure between wild-type and S1P2−/− mice, measured in awake mice. Cardiac function, evaluated in situ by using a Millar catheter, was also not different in S1P2−/− mice under baseline or stimulated conditions. In vivo analysis of vascular function by flowmetry revealed decreases in mesenteric and renal resistance in S1P2−/− mice, especially during vasoconstriction with phenylephrine. In intact aortic rings, the concentration-force relations for both KCl and phenylephrine were right shifted in S1P2−/− mice, whereas the maximal isometric forces were not different. By contrast, in deendothelialized rings the concentration-force relations were not different but the maximal force was significantly greater in S1P2−/− aorta. Histologically, there were no apparent differences in vascular morphology. These data suggest that the S1P2 receptor plays an important role in the function of the vasculature and is an important mediator of normal hemodynamics. This is mediated, at least in part, through an effect on the endothelium, but direct effects on vascular smooth muscle cannot be ruled out and require further investigation.

scholarly journals Impact of vascular morphology and plaque characteristics on computed tomography derived fractional flow reserve in early stage coronary artery disease

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Tsugu ◽  
K Tanaka ◽  
D Belsack ◽  
H Devos ◽  
Y Nagatomo ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Early Stage ◽  
Fractional Flow ◽  
Vascular Morphology ◽  
Flow Reserve ◽  
Vessel Morphology ◽  
Calcified Plaque ◽  
Artery Disease ◽  
Distal Vessel

Abstract Background FFRCT gradually decreases from the proximal to the distal part of a vessel and reach the pathological threshold for significant ischemia even in the absence of obstructive coronary artery disease (CAD). The exact mechanisms of such gradual FFRCT decline remain unknown. Purpose The aims of this study are (1) to clarify the mechanisms of the gradual decline of computed tomography (CT) derived fractional flow reserve (FFRCT); and (2) to identify the predictive factors of an FFRCT decline below the pathological value of 0.80 in no apparent CAD vessels. Methods A total of 1058 outpatients with suspected CAD and who underwent CT angiography (CTA) with FFRCT analysis between January 2017 and December 2019 were evaluated. Among them, 150 consecutive patients who had both a CTA coupled to an FFRCT analysis and an invasive angiogram showing <25% coronary stenosis were included for analysis. Vessels were divided into two groups according to FFRCT at the distal vessel: FFRCT >0.80 (n=317) and FFRCT ≤0.80 (n=114). ΔFFRCT was defined as the magnitude of the change in FFRCT from the proximal to the distal vessel. Plaque characterization and vessel morphology measurements were performed semi-automatically. Vessel constituents were characterized based on Hounsfield units (HU) into lumen volume (<−50 HU), non-calcified plaque (NCP) (−50–150 HU), and calcified plaque (>150 HU). Results FFRCT decreased continuously from the proximal to distal across the three major vessels in both FFRCT>0.80 and FFRCT ≤0.80 groups (Figure 1). Compared to FFRCT>0.80 group, NCP volume was significantly higher in all three major vessels in FFRCT ≤0.80 group (210.2±83.6 mm3 vs. 140.9±139.3 mm3 for the RCA, p=0.01; 177.5±150.2 mm3 vs. 133.2±112.2 mm3 for the LAD, p=0.04; 127.6±91.5 mm3 vs. 58.7±57.7 mm3 for the LCX, p<0.01). Next, we investigated the vessel parameters that correlated with ΔFFRCT. ΔFFRCT was correlated with lumen volume in FFRCT>0.80 group (r=−0.24, p<0.0001), whereas ΔFFRCT was correlated with NCP volume in FFRCT ≤0.80 group (r=0.42, p<0.001) (Figure 2). An NCP volume above 44.8 mm3 was the strongest predictor of distal FFRCT of ≤0.80 (area under the curve 0.69, p<0.0001, sensitivity 95%, specificity 39%). Conclusions FFRCT is affected by vascular morphology and plaque characteristics even in the early stage of coronary artery disease. Our study highlights that subclinical coronary artery disease strongly influences FFRCT by effects unrelated to coronary stenosis. The presence of NCP is a major predictor of the gradual decrease of FFRCT toward pathological values. Anatomical findings as vessel morphology and plaque characteristics should be taken into consideration when interpreting numerical values of FFRCT to avoid unnecessary referrals for invasive coronary angiography or percutaneous coronary intervention. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

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