Novel three-dimensional analysis tool for vascular trees indicates complete micro-networks, not single capillaries, as the angiogenic endpoint in mice overexpressing human VEGF165 in the brain

Heinzer, Stefan; Kuhn, Gisela; Krucker, Thomas; Meyer, Éric P.; Ulmann-Schuler, Alexandra; Stampanoni, Marco; Gassmann, Max; Marti, Hugo H.; Müller, Ralph; Vogel, Johannes

doi:10.1016/j.neuroimage.2007.10.054

Cited by 65 publications

(94 citation statements)

References 41 publications

(50 reference statements)

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“…For example, the median tumor vessel branch length is significantly shorter than that of the contralateral ROI for both D12 and D17 groups, which is consistent with observations reported in other studies (Heinzer et al, 2008;Zhang et al, 2009). However, the vessel lengths computed in this study are longer than those computed using other methods such as mCT and optical microscopy.…”

Section: Discussionsupporting

confidence: 92%

“…This effect is likely compounded by differences in ROI volumes used by different studies. For example, previous studies obtained their measurements from SRmCT images of 1 mm 3 ROIs (Heinzer et al, 2008) or from laser scanning confocal microscopy images of 100-mm-thick sections (Zhang et al, 2009), whereas we performed our analysis on ROIs that encompass D12 D17 (Panels E and F) ADC and (panels G and H) FA maps of the slices shown in panels C and D), respectively, overlaid with 3D renderings of coregistered vasculature in green. Gray scale bars are omitted for clarity and are the same as shown in Figure 4.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have used micro-CT (mCT) to image the whole 3D mouse cerebral vasculature for various applications, including creating a vascular atlas integrated with an MRI brain atlas (Dorr et al, 2007), characterizing the vascular architecture of transgenic mice (Heinzer et al, 2008), and measuring cerebral blood volume (Chugh et al, 2009). Recently, a hierarchical imaging method was developed that involved using synchrotron radiation mCT (SRmCT) to image corrosion casts of 3D capillary networks at 1.4 mm resolution in select regions of interest (ROIs) 1 mm 3 in size (Heinzer et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI)

Kim

Zhang

Hong

et al. 2011

J Cereb Blood Flow Metab

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Abnormal vascular phenotypes have been implicated in neuropathologies ranging from Alzheimer's disease to brain tumors. The development of transgenic mouse models of such diseases has created a crucial need for characterizing the murine neurovasculature. Although histologic techniques are excellent for imaging the microvasculature at submicron resolutions, they offer only limited coverage. It is also challenging to reconstruct the three-dimensional (3D) vasculature and other structures, such as white matter tracts, after tissue sectioning. Here, we describe a novel method for 3D whole-brain mapping of the murine vasculature using magnetic resonance microscopy (lMRI), and its application to a preclinical brain tumor model. The 3D vascular architecture was characterized by six morphologic parameters: vessel length, vessel radius, microvessel density, length per unit volume, fractional blood volume, and tortuosity. Region-of-interest analysis showed significant differences in the vascular phenotype between the tumor and the contralateral brain, as well as between postinoculation day 12 and day 17 tumors. These results unequivocally show the feasibility of using lMRI to characterize the vascular phenotype of brain tumors. Finally, we show that combining these vascular data with coregistered images acquired with diffusion-weighted MRI provides a new tool for investigating the relationship between angiogenesis and concomitant changes in the brain tumor microenvironment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI)

Kim

Zhang

Hong

et al. 2011

J Cereb Blood Flow Metab

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“…Occasionally, the same deposits displayed typical features of pompons and cubes combined. No similar structures were found in age-matched WT animals or in aged normal C57BL/6J or other mutant mice [e.g., IL6 or VEGF tg mice (29,30)] that were processed in parallel for other studies. Thus, pompons and cubes were considered unique to APP tg mice.…”

Section: Vessel Eliminations Forming Holes Associated With Angiogenesismentioning

confidence: 99%

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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230

215

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Substantial evidence from epidemiological, pathological, and clinical reports suggests that vascular factors are critical in the pathogenesis of Alzheimer's disease (AD), and changes in blood flow are currently the most reliable indicators of the disease. We previously reported that older APP23 transgenic (tg) mice have significant blood flow alterations correlated with structural modifications of blood vessels. For the present study, our objective was to analyze the age-dependent morphological and architectural changes of the cerebral vasculature of APP23 tg mice. To visualize the 3D arrangement of the entire brain vasculature, we used vascular corrosion casts. Already at young ages, when typically parenchymal amyloid plaques are not yet present, APP23 tg mice had significant alterations, particularly of the microvasculature, often accompanied by small deposits attached to the vessels. In older animals, vasculature abruptly ended at amyloid plaques, resulting in holes. Often, small deposits were sitting near or at the end of truncated vessels. Between such holes, the surrounding vascular array appeared more dense and showed features typical for angiogenesis. We propose that small amyloid aggregates associated with the microvasculature lead to morphological and architectural alterations of the vasculature, resulting in altered local blood flow. The characteristic early onset of vascular alterations suggests that imaging blood flow and/or vasculature architecture could be used as a tool for early diagnosis of the disease and to monitor therapies. amyloid precursor protein ͉ cerebral blood flow ͉ scanning electron microscopy ͉ vascular corrosion casting T he typical clinical picture of Alzheimer's disease (AD) includes a progressive decline of memory function, often accompanied by other clinical signs such as agitation, aggression, sleep disturbances, and social withdrawal. Nonetheless, brain autopsy is needed to positively confirm the diagnosis (1). A high density of neuritic plaques, neurofibrillary tangles, and vascular amyloid (A␤) is a characteristic neuropathological marker of AD (2, 3). Plaques and tangles in the neuropil may affect neuronal function and also contribute to the neuronal damage; however, it is unclear whether their incidence correlates with the clinical signs and symptoms of cognitive impairment characteristic of the disease (4). Evidence suggests that cerebrovascular pathologies, such as structural alterations (5), atherosclerotic lesions (6), and impaired hemodynamic responses (7), are early features of AD (for review, see ref. 8). Reduced blood flow has been reported as one of the most consistent physiological deficits in AD (9, 10); however, it remains unclear whether the reduced cerebral blood flow is a response to neuronal damage or a factor initiating the characteristic neuropathology. In vivo studies showed the effect of A␤ on cerebral blood flow and vessel architecture in a mouse model for AD (11,12). In other models, cerebrovascular regulatory mechanisms, such as endothelium-depende...

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“…Taken together, our results provide evidence for a mechanism of angiogenesis and subsequent vascular remodeling that results in capillary micro-network insertion into the mouse brain vasculature, similar to what we previously observed. 17 …”

Section: Introductionmentioning

confidence: 99%

Nogo-A regulates vascular network architecture in the postnatal brain

Wälchli

Ulmann-Schuler

Hintermüller

et al. 2016

J Cereb Blood Flow Metab

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Recently, we discovered a new role for the well-known axonal growth inhibitory molecule Nogo-A as a negative regulator of angiogenesis in the developing central nervous system. However, how Nogo-A affected the three-dimensional (3D) central nervous system (CNS) vascular network architecture remained unknown. Here, using vascular corrosion casting, hierarchical, synchrotron radiation mCT-based network imaging and computer-aided network analysis, we found that genetic ablation of Nogo-A significantly increased the three-dimensional vascular volume fraction in the postnatal day 10 (P10) mouse brain. More detailed analysis of the cerebral cortex revealed that this effect was mainly due to an increased number of capillaries and capillary branchpoints. Interestingly, other vascular parameters such as vessel diameter, -length, -tortuosity, and -volume were comparable between both genotypes for non-capillary vessels and capillaries. Taken together, our three-dimensional data showing more vessel segments and branchpoints at unchanged vessel morphology suggest that stimulated angiogenesis upon Nogo-A gene deletion results in the insertion of complete capillary micro-networks and not just single vessels into existing vascular networks. These findings significantly enhance our understanding of how angiogenesis, vascular remodeling, and three-dimensional vessel network architecture are regulated during central nervous system development. Nogo-A may therefore be a potential novel target for angiogenesis-dependent central nervous system pathologies such as brain tumors or stroke.

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Novel three-dimensional analysis tool for vascular trees indicates complete micro-networks, not single capillaries, as the angiogenic endpoint in mice overexpressing human VEGF165 in the brain

Cited by 65 publications

References 41 publications

Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI)

Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI)

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Nogo-A regulates vascular network architecture in the postnatal brain

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