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Imaging the time course, morphology, neuronal tissue compression, and resolution of cerebral microhemorrhages in mice using intravital two-photon microscopy: insights into arteriolar, capillary, and venular origin

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Abstract

Cerebral microhemorrhages (CMHs, microbleeds), a manifestation of age-related cerebral small vessel disease, contribute to the pathogenesis of cognitive decline and dementia in older adults. Histological studies have revealed that CMHs exhibit distinct morphologies, which may be attributed to differences in intravascular pressure and the size of the vessels of origin. Our study aimed to establish a direct relationship between the size/morphology of CMHs and the size/anatomy of the microvessel of origin. To achieve this goal, we adapted and optimized intravital two-photon microscopy-based imaging methods to monitor the development of CMHs in mice equipped with a chronic cranial window upon high-energy laser light-induced photodisruption of a targeted cortical arteriole, capillary, or venule. We assessed the time course of extravasation of fluorescently labeled blood and determined the morphology and size/volume of the induced CMHs. Our findings reveal striking similarities between the bleed morphologies observed in hypertension-induced CMHs in models of aging and those originating from different targeted vessels via multiphoton laser ablation. Arteriolar bleeds, which are larger (> 100 μm) and more widely dispersed, are distinguished from venular bleeds, which are smaller and exhibit a distinct diffuse morphology. Capillary bleeds are circular and smaller (< 10 μm) in size. Our study supports the concept that CMHs can occur at any location in the vascular tree, and that each type of vessel produces microbleeds with a distinct morphology. Development of CMHs resulted in immediate constriction of capillaries, likely due to pericyte activation and constriction of precapillary arterioles. Additionally, tissue displacement observed in association with arteriolar CMHs suggests that they can affect an area with a radius of ~ 50 μm to ~ 100 μm, creating an area at risk for ischemia. Longitudinal imaging of CMHs allowed us to visualize reactive astrocytosis and bleed resolution during a 30-day period. Our study provides new insights into the development and morphology of CMHs, highlighting the potential clinical implications of differentiating between the types of vessels involved in the pathogenesis of CMHs. This information may help in the development of targeted interventions aimed at reducing the risk of cerebral small vessel disease-related cognitive decline and dementia in older adults.

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Funding

This work was supported by grants from the American Heart Association (ANT: AHA834339), the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614), the National Institute of Neurological Disorders and Stroke (R01NS100782), the National Cancer Institute (R01CA255840), the Oklahoma Shared Clinical and Translational Resources (U54GM104938) with an Institutional Development Award (IDeA) from NIGMS, the Presbyterian Health Foundation, the Reynolds Foundation, the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (P20GM125528). PT was also supported by grants from the National Research, Development and Innovation Office (OTKA K-134555), the Hungarian Academy of Sciences Bolyai Research Scholarship, National Clinical Neuroscience Laboratory (RRF-2.3.1–21-2022–00011), and the Thematic Excellence Program 2021 Health Sub-programme of the Ministry for Innovation and Technology in Hungary, within the framework of the EGA-16 project of the University of Pecs. Support was also provided by Project no. TKP2021-NKTA-47, implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NKTA funding scheme; by funding through the National Cardiovascular Laboratory Program (RRF-2.3.1–21-2022–00003) provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund; Project no. 135784 implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the K_20 funding scheme and the European University for Well-Being (EUniWell) program (grant agreement number: 101004093/ EUniWell/EAC-A02-2019 / EAC-A02-2019–1). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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  1. Janet Faakye and Ádám Nyúl-Tóth have equal contributions.

Authors and Affiliations

  1. Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Janet Faakye, Ádám Nyúl-Tóth, Rafal Gulej, Boglarka Csik, Stefano Tarantini, Santny Shanmugarama, Peter Mukli, Andriy Yabluchanskiy, Peter Toth, Anna Csiszar & Zoltan Ungvari

  2. Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Janet Faakye, Ádám Nyúl-Tóth, Rafal Gulej, Boglarka Csik, Stefano Tarantini, Santny Shanmugarama, Peter Mukli, Andriy Yabluchanskiy, Shannon Conley, Peter Toth, Anna Csiszar & Zoltan Ungvari

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Ádám Nyúl-Tóth, Rafal Gulej, Boglarka Csik, Stefano Tarantini & Zoltan Ungvari

  4. Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA

    Stefano Tarantini, Anna Csiszar & Zoltan Ungvari

  5. Veterans Affairs Medical Center, Oklahoma City, OK, USA

    Calin Prodan

  6. Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Calin Prodan

  7. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Shannon Conley

  8. Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary

    Peter Toth

  9. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary

    Anna Csiszar

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  1. Janet Faakye
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Correspondence to Ádám Nyúl-Tóth or Zoltan Ungvari.

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Dr. Anna Csiszar serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience and as Consulting Editor for The American Journal of Physiology-Heart and Circulatory Physiology. Dr. Stefano Tarantini, Dr. Shannon Conley and Dr. Andriy Yabluchanskiy serve as Associate Editors for GeroScience.

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Faakye, J., Nyúl-Tóth, Á., Gulej, R. et al. Imaging the time course, morphology, neuronal tissue compression, and resolution of cerebral microhemorrhages in mice using intravital two-photon microscopy: insights into arteriolar, capillary, and venular origin. GeroScience 45, 2851–2872 (2023). https://doi.org/10.1007/s11357-023-00839-w

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