{"id":{"repo_id":"edinburgh","oai_identifier":"oai:era.ed.ac.uk:1842/41085"},"canonical_url":"https://search.dev.ndltd.org/etd/edinburgh/oai:era.ed.ac.uk:1842/41085","repository":{"repo_id":"edinburgh","name":"University of Edinburgh","base_url":"https://era.ed.ac.uk/server/oai/request"},"display":{"title":"Abnormal microvascular phenotypes in a mouse model of glioblastoma and the effect of vessel compression on blood flow","abstract":"Cancer is a major healthcare concern in the world, accounting for one in six deaths. Despite this, cancer patient survival rates have increased over the past decades as a result of healthcare improvement reforms and advances in medical research. Among the numerous areas of research in cancer, studying the tumour microenvironment and the physics of cancer has shown promising results for patient benefit, and will be the focus of this thesis. A tumour is an abnormal cell growth, and is cancerous when it has the potential to metastasise. Tumours have their own microenvironment which presents numerous abnormalities compared to healthy tissue. In particular, as tumours grow they develop their own microvascular system to transport nutrients and oxygen to the cells. However, the tumour vasculature is abnormal and inefficient, leading to an abnormal microenvironment, with traits such as hypoxia. Hypoxia leads to more aggressive tumours and is a barrier to treatment, making it an undesirable trait. A better understanding of the causes of tumour hypoxia could thus benefit patient care. One tumour vessel abnormality is vessel compression, which is the result of high solid stress in tumours. Studies have shown that vessel compression correlates with reduced survival rates, and increased hypoxia and oxygen heterogeneity. However, the biophysical mechanism which links compressed vessels to hypoxia is not clear. In addition, vessel compression has not been characterised in glioblastoma multiforme brain tumours, despite the correlation between vessel compression and reduced survival rates, and the low survival rates of glioblastoma patients. As red blood cells transport oxygen in blood, the central hypothesis of this thesis is that vessel compression leads to abnormal transport of red blood cells, contributing to tissue hypoxia. Therefore, the aim of this work is to find a mechanistic link between vessel compression and abnormal red blood cell transport in compressed vascular networks and contextualise it to glioblastoma. The first results chapter investigates the effect of a compression on the partitioning of red blood cells at a downstream bifurcation. The numerical experiment shows that, with a compressed parent branch, the higher flowing child branch is enriched in red blood cells compared to a control simulation. The abnormal partitioning of red blood cells is the result of a narrowing of the red blood cell cross-sectional distribution as they enter the compression. Indeed, in the compression the red blood cells undergo cross-streamline migration to more central streamlines as a result of the increased shear rate and shear rate gradient in the compression. The results further show that the abnormal partitioning of red blood cells is present over a wide range of flow ratios to the child branches. The abnormal partitioning of red blood cells becomes less pronounced as the parent branch haematocrit increases, up to a critical threshold of around 30%, above which abnormal partitioning no longer occurs. The second results chapter builds on to the first one and numerically investigates how the abnormal partitioning of red blood cells at a single bifurcation propagates at a network level. To do so, it adapts and validates an existing reduced-order model to accurately and efficiently calculate the abnormal partitioning of red blood cells when parent branches are compressed. At a network level, and compared to a control, vessel compression increases haematocrit heterogeneity, reduces the average haematocrit, and increases the number of plasma channels present. The mechanisms for these findings are investigated and show that both the increased resistance to flow and the abnormal partitioning of red blood cells at a bifurcation contribute to lowering the haematocrit in the networks, but that haematocrit heterogeneity is only the result of the abnormal partitioning of red blood cells. Finally, it is shown that the reduction in average haematocrit in the networks occurs over a wide range of inlet haematocrits, and that only a relatively small number of vessels need to be compressed for the reduction to be present. The final results chapter phenotypes and compares the microvasculature in a mouse model of a glioblastoma to control mice. A pipeline is developed and validated to reconstruct the threedimensional vessel surfaces from multiphoton microscopy images of the vasculature. The data show that the non-dimensional interbifurcation distance and the mean tissue-vessel distance are significantly lower in tumours, but that other phenotypes are not different. Notably, the tumour vessels were not compressed. Furthermore, the results show that there is a correlation between the mean tissue-vessel distance in a region of interest and the distance of the region of interest from the tumour core. Taken together, these findings address the aim of this thesis and provide a mechanism for abnormal transport of red blood cells in compressed vessel networks. Due to the importance of red blood cells in the transport of oxygen, this work contributes to the knowledge of the causes of hypoxia in tumours with vessel compression. As hypoxia is an important trait adversely affecting patient prognosis, understanding the mechanisms leading to hypoxia has the potential, in the long term, to inform patient care.","abstract_html":"Cancer is a major healthcare concern in the world, accounting for one in six deaths. Despite this, cancer patient survival rates have increased over the past decades as a result of healthcare improvement reforms and advances in medical research. Among the numerous areas of research in cancer, studying the tumour microenvironment and the physics of cancer has shown promising results for patient benefit, and will be the focus of this thesis. A tumour is an abnormal cell growth, and is cancerous when it has the potential to metastasise. Tumours have their own microenvironment which presents numerous abnormalities compared to healthy tissue. In particular, as tumours grow they develop their own microvascular system to transport nutrients and oxygen to the cells. However, the tumour vasculature is abnormal and inefficient, leading to an abnormal microenvironment, with traits such as hypoxia. Hypoxia leads to more aggressive tumours and is a barrier to treatment, making it an undesirable trait. A better understanding of the causes of tumour hypoxia could thus benefit patient care. One tumour vessel abnormality is vessel compression, which is the result of high solid stress in tumours. Studies have shown that vessel compression correlates with reduced survival rates, and increased hypoxia and oxygen heterogeneity. However, the biophysical mechanism which links compressed vessels to hypoxia is not clear. In addition, vessel compression has not been characterised in glioblastoma multiforme brain tumours, despite the correlation between vessel compression and reduced survival rates, and the low survival rates of glioblastoma patients. As red blood cells transport oxygen in blood, the central hypothesis of this thesis is that vessel compression leads to abnormal transport of red blood cells, contributing to tissue hypoxia. Therefore, the aim of this work is to find a mechanistic link between vessel compression and abnormal red blood cell transport in compressed vascular networks and contextualise it to glioblastoma. The first results chapter investigates the effect of a compression on the partitioning of red blood cells at a downstream bifurcation. The numerical experiment shows that, with a compressed parent branch, the higher flowing child branch is enriched in red blood cells compared to a control simulation. The abnormal partitioning of red blood cells is the result of a narrowing of the red blood cell cross-sectional distribution as they enter the compression. Indeed, in the compression the red blood cells undergo cross-streamline migration to more central streamlines as a result of the increased shear rate and shear rate gradient in the compression. The results further show that the abnormal partitioning of red blood cells is present over a wide range of flow ratios to the child branches. The abnormal partitioning of red blood cells becomes less pronounced as the parent branch haematocrit increases, up to a critical threshold of around 30%, above which abnormal partitioning no longer occurs. The second results chapter builds on to the first one and numerically investigates how the abnormal partitioning of red blood cells at a single bifurcation propagates at a network level. To do so, it adapts and validates an existing reduced-order model to accurately and efficiently calculate the abnormal partitioning of red blood cells when parent branches are compressed. At a network level, and compared to a control, vessel compression increases haematocrit heterogeneity, reduces the average haematocrit, and increases the number of plasma channels present. The mechanisms for these findings are investigated and show that both the increased resistance to flow and the abnormal partitioning of red blood cells at a bifurcation contribute to lowering the haematocrit in the networks, but that haematocrit heterogeneity is only the result of the abnormal partitioning of red blood cells. Finally, it is shown that the reduction in average haematocrit in the networks occurs over a wide range of inlet haematocrits, and that only a relatively small number of vessels need to be compressed for the reduction to be present. The final results chapter phenotypes and compares the microvasculature in a mouse model of a glioblastoma to control mice. A pipeline is developed and validated to reconstruct the threedimensional vessel surfaces from multiphoton microscopy images of the vasculature. The data show that the non-dimensional interbifurcation distance and the mean tissue-vessel distance are significantly lower in tumours, but that other phenotypes are not different. Notably, the tumour vessels were not compressed. Furthermore, the results show that there is a correlation between the mean tissue-vessel distance in a region of interest and the distance of the region of interest from the tumour core. Taken together, these findings address the aim of this thesis and provide a mechanism for abnormal transport of red blood cells in compressed vessel networks. Due to the importance of red blood cells in the transport of oxygen, this work contributes to the knowledge of the causes of hypoxia in tumours with vessel compression. As hypoxia is an important trait adversely affecting patient prognosis, understanding the mechanisms leading to hypoxia has the potential, in the long term, to inform patient care.","abstract_has_math":false,"creators":["Enjalbert, Romain"],"institution":"The University of Edinburgh","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Bernabeu, Miguel O.","Krueger, Timm","Kersaudy-Kerhoas, Maiwenn"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-10-20","date_published":"2023-10-20","updated_at":"2026-07-24T02:13:53Z","subjects":["Abnormal microvascular phenotypes","mouse model of glioblastoma","vessel compression","blood flow","Cancer","tumour microenvironment","tumour vasculature","Hypoxia","high solid stress","oxygen heterogeneity","glioblastoma","glioblastoma multiforme brain tumours"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://dx.doi.org/10.7488/era/3824"],"render_values":[{"text":"http://dx.doi.org/10.7488/era/3824","href":"http://dx.doi.org/10.7488/era/3824","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1842/41085","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Bernabeu, Miguel O.","Krueger, Timm","Kersaudy-Kerhoas, Maiwenn"]},{"key":"dc:creator","label":"Author","values":["Enjalbert, Romain"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-10-20T11:39:41Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2023-10-20T11:39:41Z"]},{"key":"dc:date.issued","label":"Date","values":["2023-10-20"]},{"key":"dc:publisher","label":"Institution","values":["The University of Edinburgh"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or Dissertation"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD Doctor of Philosophy"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Abnormal microvascular phenotypes","mouse model of glioblastoma","vessel compression","blood flow","Cancer","tumour microenvironment","tumour vasculature","Hypoxia","high solid stress","oxygen heterogeneity","glioblastoma","glioblastoma multiforme brain tumours"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1842/41085","http://dx.doi.org/10.7488/era/3824"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cancer is a major healthcare concern in the world, accounting for one in six deaths. Despite this, cancer patient survival rates have increased over the past decades as a result of healthcare improvement reforms and advances in medical research. Among the numerous areas of research in cancer, studying the tumour microenvironment and the physics of cancer has shown promising results for patient benefit, and will be the focus of this thesis. A tumour is an abnormal cell growth, and is cancerous when it has the potential to metastasise. Tumours have their own microenvironment which presents numerous abnormalities compared to healthy tissue. In particular, as tumours grow they develop their own microvascular system to transport nutrients and oxygen to the cells. However, the tumour vasculature is abnormal and inefficient, leading to an abnormal microenvironment, with traits such as hypoxia. Hypoxia leads to more aggressive tumours and is a barrier to treatment, making it an undesirable trait. A better understanding of the causes of tumour hypoxia could thus benefit patient care. One tumour vessel abnormality is vessel compression, which is the result of high solid stress in tumours. Studies have shown that vessel compression correlates with reduced survival rates, and increased hypoxia and oxygen heterogeneity. However, the biophysical mechanism which links compressed vessels to hypoxia is not clear. In addition, vessel compression has not been characterised in glioblastoma multiforme brain tumours, despite the correlation between vessel compression and reduced survival rates, and the low survival rates of glioblastoma patients. As red blood cells transport oxygen in blood, the central hypothesis of this thesis is that vessel compression leads to abnormal transport of red blood cells, contributing to tissue hypoxia. Therefore, the aim of this work is to find a mechanistic link between vessel compression and abnormal red blood cell transport in compressed vascular networks and contextualise it to glioblastoma. The first results chapter investigates the effect of a compression on the partitioning of red blood cells at a downstream bifurcation. The numerical experiment shows that, with a compressed parent branch, the higher flowing child branch is enriched in red blood cells compared to a control simulation. The abnormal partitioning of red blood cells is the result of a narrowing of the red blood cell cross-sectional distribution as they enter the compression. Indeed, in the compression the red blood cells undergo cross-streamline migration to more central streamlines as a result of the increased shear rate and shear rate gradient in the compression. The results further show that the abnormal partitioning of red blood cells is present over a wide range of flow ratios to the child branches. The abnormal partitioning of red blood cells becomes less pronounced as the parent branch haematocrit increases, up to a critical threshold of around 30%, above which abnormal partitioning no longer occurs. The second results chapter builds on to the first one and numerically investigates how the abnormal partitioning of red blood cells at a single bifurcation propagates at a network level. To do so, it adapts and validates an existing reduced-order model to accurately and efficiently calculate the abnormal partitioning of red blood cells when parent branches are compressed. At a network level, and compared to a control, vessel compression increases haematocrit heterogeneity, reduces the average haematocrit, and increases the number of plasma channels present. The mechanisms for these findings are investigated and show that both the increased resistance to flow and the abnormal partitioning of red blood cells at a bifurcation contribute to lowering the haematocrit in the networks, but that haematocrit heterogeneity is only the result of the abnormal partitioning of red blood cells. Finally, it is shown that the reduction in average haematocrit in the networks occurs over a wide range of inlet haematocrits, and that only a relatively small number of vessels need to be compressed for the reduction to be present. The final results chapter phenotypes and compares the microvasculature in a mouse model of a glioblastoma to control mice. A pipeline is developed and validated to reconstruct the threedimensional vessel surfaces from multiphoton microscopy images of the vasculature. The data show that the non-dimensional interbifurcation distance and the mean tissue-vessel distance are significantly lower in tumours, but that other phenotypes are not different. Notably, the tumour vessels were not compressed. Furthermore, the results show that there is a correlation between the mean tissue-vessel distance in a region of interest and the distance of the region of interest from the tumour core. Taken together, these findings address the aim of this thesis and provide a mechanism for abnormal transport of red blood cells in compressed vessel networks. Due to the importance of red blood cells in the transport of oxygen, this work contributes to the knowledge of the causes of hypoxia in tumours with vessel compression. As hypoxia is an important trait adversely affecting patient prognosis, understanding the mechanisms leading to hypoxia has the potential, in the long term, to inform patient care."]},{"key":"dc:title","label":"Title","values":["Abnormal microvascular phenotypes in a mouse model of glioblastoma and the effect of vessel compression on blood flow"]}]}],"canonical_facts":{"dc:contributor.advisor":["Bernabeu, Miguel O.","Krueger, Timm","Kersaudy-Kerhoas, Maiwenn"],"dc:creator":["Enjalbert, Romain"],"dc:date.accessioned":["2023-10-20T11:39:41Z"],"dc:date.available":["2023-10-20T11:39:41Z"],"dc:date.issued":["2023-10-20"],"dc:description.abstract":["Cancer is a major healthcare concern in the world, accounting for one in six deaths. Despite this, cancer patient survival rates have increased over the past decades as a result of healthcare improvement reforms and advances in medical research. Among the numerous areas of research in cancer, studying the tumour microenvironment and the physics of cancer has shown promising results for patient benefit, and will be the focus of this thesis. A tumour is an abnormal cell growth, and is cancerous when it has the potential to metastasise. Tumours have their own microenvironment which presents numerous abnormalities compared to healthy tissue. In particular, as tumours grow they develop their own microvascular system to transport nutrients and oxygen to the cells. However, the tumour vasculature is abnormal and inefficient, leading to an abnormal microenvironment, with traits such as hypoxia. Hypoxia leads to more aggressive tumours and is a barrier to treatment, making it an undesirable trait. A better understanding of the causes of tumour hypoxia could thus benefit patient care. One tumour vessel abnormality is vessel compression, which is the result of high solid stress in tumours. Studies have shown that vessel compression correlates with reduced survival rates, and increased hypoxia and oxygen heterogeneity. However, the biophysical mechanism which links compressed vessels to hypoxia is not clear. In addition, vessel compression has not been characterised in glioblastoma multiforme brain tumours, despite the correlation between vessel compression and reduced survival rates, and the low survival rates of glioblastoma patients. As red blood cells transport oxygen in blood, the central hypothesis of this thesis is that vessel compression leads to abnormal transport of red blood cells, contributing to tissue hypoxia. Therefore, the aim of this work is to find a mechanistic link between vessel compression and abnormal red blood cell transport in compressed vascular networks and contextualise it to glioblastoma. The first results chapter investigates the effect of a compression on the partitioning of red blood cells at a downstream bifurcation. The numerical experiment shows that, with a compressed parent branch, the higher flowing child branch is enriched in red blood cells compared to a control simulation. The abnormal partitioning of red blood cells is the result of a narrowing of the red blood cell cross-sectional distribution as they enter the compression. Indeed, in the compression the red blood cells undergo cross-streamline migration to more central streamlines as a result of the increased shear rate and shear rate gradient in the compression. The results further show that the abnormal partitioning of red blood cells is present over a wide range of flow ratios to the child branches. The abnormal partitioning of red blood cells becomes less pronounced as the parent branch haematocrit increases, up to a critical threshold of around 30%, above which abnormal partitioning no longer occurs. The second results chapter builds on to the first one and numerically investigates how the abnormal partitioning of red blood cells at a single bifurcation propagates at a network level. To do so, it adapts and validates an existing reduced-order model to accurately and efficiently calculate the abnormal partitioning of red blood cells when parent branches are compressed. At a network level, and compared to a control, vessel compression increases haematocrit heterogeneity, reduces the average haematocrit, and increases the number of plasma channels present. The mechanisms for these findings are investigated and show that both the increased resistance to flow and the abnormal partitioning of red blood cells at a bifurcation contribute to lowering the haematocrit in the networks, but that haematocrit heterogeneity is only the result of the abnormal partitioning of red blood cells. Finally, it is shown that the reduction in average haematocrit in the networks occurs over a wide range of inlet haematocrits, and that only a relatively small number of vessels need to be compressed for the reduction to be present. The final results chapter phenotypes and compares the microvasculature in a mouse model of a glioblastoma to control mice. A pipeline is developed and validated to reconstruct the threedimensional vessel surfaces from multiphoton microscopy images of the vasculature. The data show that the non-dimensional interbifurcation distance and the mean tissue-vessel distance are significantly lower in tumours, but that other phenotypes are not different. Notably, the tumour vessels were not compressed. Furthermore, the results show that there is a correlation between the mean tissue-vessel distance in a region of interest and the distance of the region of interest from the tumour core. Taken together, these findings address the aim of this thesis and provide a mechanism for abnormal transport of red blood cells in compressed vessel networks. Due to the importance of red blood cells in the transport of oxygen, this work contributes to the knowledge of the causes of hypoxia in tumours with vessel compression. As hypoxia is an important trait adversely affecting patient prognosis, understanding the mechanisms leading to hypoxia has the potential, in the long term, to inform patient care."],"dc:identifier.uri":["https://hdl.handle.net/1842/41085","http://dx.doi.org/10.7488/era/3824"],"dc:language.iso":["en"],"dc:publisher":["The University of Edinburgh"],"dc:subject":["Abnormal microvascular phenotypes","mouse model of glioblastoma","vessel compression","blood flow","Cancer","tumour microenvironment","tumour vasculature","Hypoxia","high solid stress","oxygen heterogeneity","glioblastoma","glioblastoma multiforme brain tumours"],"dc:title":["Abnormal microvascular phenotypes in a mouse model of glioblastoma and the effect of vessel compression on blood flow"],"dc:type":["Thesis or Dissertation"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD Doctor of Philosophy"]},"updated_at":"2026-07-24T02:13:53Z"}