Spectral imaging reveals microvessel physiology and function from anastomoses to thromboses

Wankhede, Mamta; Agarwal, Nikita; Fraga‐Silva, Rodrigo A.; deDeugd, Casey; Raizada, Mohan K.; Oh, S. Paul; Sorg, Brian S.

doi:10.1117/1.3316299

Cited by 15 publications

(15 citation statements)

References 91 publications

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“…Based on the illumination wavelength dependence of IOS [7] we assume that mainly the light scattering component of in vitro afferent evoked IOS was detected at 700 nm. Measuring at this wavelength has the advantage of the deeper penetration into the slice and the reduced contribution of the absorption of the residual hemoglobin (usually measured at 600−660 nm [72], [73], [74]) and the intrinsic cytochromes such porphyrins (maximal absorption wavelengths 440 nm [15]). As dendritic beading and changes of mitochondrial architecture are usually coupled by strong activation (i.e.…”

Section: Discussionmentioning

confidence: 99%

Neuronal and Astroglial Correlates Underlying Spatiotemporal Intrinsic Optical Signal in the Rat Hippocampal Slice

et al. 2013

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Widely used for mapping afferent activated brain areas in vivo, the label-free intrinsic optical signal (IOS) is mainly ascribed to blood volume changes subsequent to glial glutamate uptake. By contrast, IOS imaged in vitro is generally attributed to neuronal and glial cell swelling, however the relative contribution of different cell types and molecular players remained largely unknown. We characterized IOS to Schaffer collateral stimulation in the rat hippocampal slice using a 464-element photodiode-array device that enables IOS monitoring at 0.6 ms time-resolution in combination with simultaneous field potential recordings. We used brief half-maximal stimuli by applying a medium intensity 50 Volt-stimulus train within 50 ms (20 Hz). IOS was primarily observed in the str. pyramidale and proximal region of the str. radiatum of the hippocampus. It was eliminated by tetrodotoxin blockade of voltage-gated Na+ channels and was significantly enhanced by suppressing inhibitory signaling with gamma-aminobutyric acid(A) receptor antagonist picrotoxin. We found that IOS was predominantly initiated by postsynaptic Glu receptor activation and progressed by the activation of astroglial Glu transporters and Mg2+-independent astroglial N-methyl-D-aspartate receptors. Under control conditions, role for neuronal K+/Cl− cotransporter KCC2, but not for glial Na+/K+/Cl− cotransporter NKCC1 was observed. Slight enhancement and inhibition of IOS through non-specific Cl− and volume-regulated anion channels, respectively, were also depicted. High-frequency IOS imaging, evoked by brief afferent stimulation in brain slices provide a new paradigm for studying mechanisms underlying IOS genesis. Major players disclosed this way imply that spatiotemporal IOS reflects glutamatergic neuronal activation and astroglial response, as observed within the hippocampus. Our model may help to better interpret in vivo IOS and support diagnosis in the future.

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Section: Discussionmentioning

confidence: 99%

Neuronal and Astroglial Correlates Underlying Spatiotemporal Intrinsic Optical Signal in the Rat Hippocampal Slice

et al. 2013

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“…Studies have shown that hypoxic vessels are associated with tumor angiogenesis, progression, stem cell induction/protection, metastasis and possibly revascularization of recurrent tumors [ 4 , 6 – 10 , 34 ]. The realization that hypoxic microvasculature exists as early as the developmental stage [ 4 , 5 ] and plays a key-role in tumor progression and treatment response, brings about new possibilities for the role of hypoxia in cancer biology. Improved radiation delivery techniques allow the potential for dose painting tumor areas found to harbor hypoxic tumor vessels.…”

Section: Discussionmentioning

confidence: 99%

Targeting Artificial Tumor Stromal Targets for Molecular Imaging of Tumor Vascular Hypoxia

et al. 2015

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Developed and tested for many years, a variety of tumor hypoxia detection methods have been inconsistent in their ability to predict treatment outcomes or monitor treatment efficacy, limiting their present prognostic capability. These variable results might stem from the fact that these approaches are based on inherently wide-ranging global tumor oxygenation levels based on uncertain influences of necrotic regions present in most solid tumors. Here, we have developed a novel non-invasive and specific method for tumor vessel hypoxia detection, as hypoxemia (vascular hypoxia) has been implicated as a key driver of malignant progression, therapy resistance and metastasis. This method is based on high-frequency ultrasound imaging of α-pimonidazole targeted-microbubbles to the exogenously administered hypoxia marker pimonidazole. The degree of tumor vessel hypoxia was assessed in three mouse models of mammary gland carcinoma (4T1, SCK and MMTV-Wnt-1) and amassed up to 20% of the tumor vasculature. In the 4T1 mammary gland carcinoma model, the signal strength of α-pimonidazole targeted-microbubbles was on average 8-fold fold higher in tumors of pimonidazole-injected mice than in non-pimonidazole injected tumor bearing mice or non-targeted microbubbles in pimonidazole-injected tumor bearing mice. Overall, this provides proof of principle for generating and targeting artificial antigens able to be ‘created’ on-demand under tumor specific microenvironmental conditions, providing translational diagnostic, therapeutic and treatment planning potential in cancer and other hypoxia-associated diseases or conditions.

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“…The new understanding of the cellular mechanisms involved in the tumor neovasculature formation provokes some additional retrospective thoughts on earlier published results regarding vasculature related issues that were also based on the model of breast tumors grown in the mouse skin fold chamber. For example, abnormal microvascular oxygen transport demonstrated by spectral imaging of hemoglobin saturation 83 , 84 . Anastomoses between vessels with significantly different oxygenations could be explained by the fusion of hypoxic capsular vaso-mimicry with a vein containing circulating blood; the direction of the flow initiated that way would be expected to be the same as in the vein involved in the fusion, as observed (Figure 8 in 84 ).…”

Section: Discussionmentioning

confidence: 99%

II. Capsular vaso-mimicry formed by transgenic mammary tumor spheroids implanted ectopically into mouse dorsal skin fold: implications for cellular mechanisms of metastasis

Witkiewicz

Schnitzer

2013

F1000Res

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Most cancer patients die of metastatic disease, not primary tumors, while biological mechanisms leading to metastases remain unclear and effective therapies are missing. Using a mouse dorsal skin chamber model we had observed that tumor growth and vasculature formation could be influenced by the way in vitro cultured (avascular) spheroids of N202 breast tumor cells were implanted; co-implantation of lactating breast tissue created stimulating microenvironment, whereas the absence of the graft resulted in temporary tumor dormancy. This report addressed the issue of cellular mechanisms of the vasculogenic switch that ended the dormancy. In situ ultrastructural analysis revealed that the tumors survived in ectopic microenvironment until some of host and tumor stem cells evolved independently into cells initiating the vasculogenic switch. The tumor cells that survived and proliferated under hypoxic conditions for three weeks were supported by erythrogenic autophagy of others. However, the host microenvironment first responded as it would to non-immunogenic foreign bodies, i.e., by encapsulating the tumor spheroids with collagen-producing fibroblasts. That led to a form of vaso-mimicry consisting of tumor cells amid tumor-derived erythrosomes (synonym of erythrocytes), megakaryocytes and platelets, and encapsulating them all, the host fibroblasts. Such capsular vaso-mimicry could potentially facilitate metastasis by fusing with morphologically similar lymphatic vessels or veins. Once incorporated into the host circulatory system, tumor cells could be carried away passively by blood flow, regardless of their genetic heterogeneity. The fake vascular segment would have permeability properties different from genuine vascular endothelium. The capsular vaso-mimicry was different from vasculogenic mimicry earlier observed in metastases-associated malignant tumors where channels formed by tumor cells were said to contain circulating blood. Structures similar to the vasculogenic mimicry were seen here as well but contained non-circulating erythrosomes formed between tumor nodules. The host’s response to the implantation included coordinated formation of new vessels and peripheral nerves.

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Spectral imaging reveals microvessel physiology and function from anastomoses to thromboses

Cited by 15 publications

References 91 publications

Neuronal and Astroglial Correlates Underlying Spatiotemporal Intrinsic Optical Signal in the Rat Hippocampal Slice

Neuronal and Astroglial Correlates Underlying Spatiotemporal Intrinsic Optical Signal in the Rat Hippocampal Slice

Targeting Artificial Tumor Stromal Targets for Molecular Imaging of Tumor Vascular Hypoxia

II. Capsular vaso-mimicry formed by transgenic mammary tumor spheroids implanted ectopically into mouse dorsal skin fold: implications for cellular mechanisms of metastasis

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