Arteriosclerosis, thrombosis, and vascular biology · 2025
Visualizing Vascular Bone Marrow Niche Alterations in Diabetes.
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Haj Narmeen, Tiwari Ashish, Berihu Maria, Kher Nedaa, Nsraldeen Siraj, Holdengreber Maya, Karni-Ashkenazi Shiri, Zhou Bin, Saar Galit, Stuckey Daniel J, Vandoorne Katrien
Аннотация
BACKGROUND: Diabetes is characterized by chronic hyperglycemia that leads to systemic vascular complications. Hyperglycemia impairs endothelial function and promotes vascular inflammation, resulting in leukocytosis, altered hematopoiesis, and cardiovascular complications. Bone marrow endothelial cells play a pivotal role in regulating myeloid progenitor cells and leukocyte trafficking. However, the effects of diabetes on the structure and function of bone marrow vasculature remain poorly understood. To address this, we used a multiscale imaging approach integrating intravital microscopy, dynamic contrast-enhanced magnetic resonance imaging, and multispectral optoacoustic tomography to investigate diabetes-induced vascular changes in the bone marrow.
METHODS: Diabetes was induced in C57BL/6J female mice using streptozotocin. Flow cytometry and histology characterized bone marrow myeloid progenitors, blood leukocytes, and bone marrow endothelial cell populations, as well as hypoxia. Intravital microscopy was used to visualize vascular density, permeability, and sprouting angiogenesis in the calvarial marrow. Dynamic contrast-enhanced magnetic resonance imaging quantified vascular density and permeability in the femoral marrow, while multispectral optoacoustic tomography assessed hemoglobin oxygenation in the calvarial marrow.
RESULTS: Hyperglycemia significantly increased myelopoiesis, leading to elevated leukocytosis driving diabetic inflammation. Flow cytometry and histology revealed increased bone marrow endothelial cell numbers (P=0.0006), while intravital microscopy showed elevated vascular permeability (P=0.0095) and sprouting angiogenesis (P=0.0095). Dynamic contrast-enhanced magnetic resonance imaging confirmed greater vascular density (P=0.019) and leakiness (P=0.0062), and multispectral optoacoustic tomography detected reduced hemoglobin oxygenation and increased hypoxia in the diabetic marrow (P=0.0065), reflecting a hypoxic niche favorable to hematopoietic stem and progenitor cells. This likely drives angiogenesis and contributes to inflammatory hematopoiesis in diabetes.
CONCLUSIONS: This study demonstrates that diabetes induces profound vascular remodeling and hypoxia in the bone marrow, reshaping the hematopoietic niche and driving myelopoiesis and leukocytosis. By validating dynamic contrast-enhanced magnetic resonance imaging and multispectral optoacoustic tomography as noninvasive translational tools, coupled with intravital microscopy, we provide a comprehensive framework for exploring novel therapies targeting bone marrow vasculature to mitigate inflammation-driven outcomes in diabetes.
METHODS: Diabetes was induced in C57BL/6J female mice using streptozotocin. Flow cytometry and histology characterized bone marrow myeloid progenitors, blood leukocytes, and bone marrow endothelial cell populations, as well as hypoxia. Intravital microscopy was used to visualize vascular density, permeability, and sprouting angiogenesis in the calvarial marrow. Dynamic contrast-enhanced magnetic resonance imaging quantified vascular density and permeability in the femoral marrow, while multispectral optoacoustic tomography assessed hemoglobin oxygenation in the calvarial marrow.
RESULTS: Hyperglycemia significantly increased myelopoiesis, leading to elevated leukocytosis driving diabetic inflammation. Flow cytometry and histology revealed increased bone marrow endothelial cell numbers (P=0.0006), while intravital microscopy showed elevated vascular permeability (P=0.0095) and sprouting angiogenesis (P=0.0095). Dynamic contrast-enhanced magnetic resonance imaging confirmed greater vascular density (P=0.019) and leakiness (P=0.0062), and multispectral optoacoustic tomography detected reduced hemoglobin oxygenation and increased hypoxia in the diabetic marrow (P=0.0065), reflecting a hypoxic niche favorable to hematopoietic stem and progenitor cells. This likely drives angiogenesis and contributes to inflammatory hematopoiesis in diabetes.
CONCLUSIONS: This study demonstrates that diabetes induces profound vascular remodeling and hypoxia in the bone marrow, reshaping the hematopoietic niche and driving myelopoiesis and leukocytosis. By validating dynamic contrast-enhanced magnetic resonance imaging and multispectral optoacoustic tomography as noninvasive translational tools, coupled with intravital microscopy, we provide a comprehensive framework for exploring novel therapies targeting bone marrow vasculature to mitigate inflammation-driven outcomes in diabetes.