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(Circulation. 2009;120:1910-1918.)
© 2009 American Heart Association, Inc.

Vascular Medicine

High Levels of Acetylated Low-Density Lipoprotein Uptake and Low Tyrosine Kinase With Immunoglobulin and Epidermal Growth Factor Homology Domains-2 (Tie2) Promoter Activity Distinguish Sinusoids From Other Vessel Types in Murine Bone Marrow

Xiao-Miao Li, PhD; Zhongbo Hu, MD, PhD; Marda L. Jorgenson, BS; William B. Slayton, MD

From the Department of Pediatrics, Division of Pediatric Hematology/Oncology (X.-M.L., Z.H., W.B.S.) and McKnight Brain Institute (M.L.J.), University of Florida, Gainesville.

Correspondence to William B. Slayton, MD, UFHSC, Box 100296, Gainesville, FL 32610. E-mail slaytwb{at}peds.ufl.edu

Received June 27, 2008; accepted August 25, 2009.

Background— The bone marrow contains a variety of blood vessels that have different functions in bone marrow maintenance and hematopoiesis. Arterioles control the flow of blood into bone marrow compartments, and sinusoids serve as a conduit to the bloodstream and as niches for megakaryocyte development. Most studies of bone marrow vasculature, including studies quantifying changes in the marrow vascular by microvascular density, do not differentiate between different types of marrow vessels. Recognizing changes in different types of blood vessels after chemotherapy exposure or during leukemia development has important physiological implications. We hypothesized that the functional heterogeneity of marrow vasculature could be recognized through the use of functional markers such as tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) expression or 1,1-dioctadecyl -3,3,3,3-tetramethyl-indocarbocyanine perchlorate with acetylated low-density lipoprotein (DiI-Ac-LDL) uptake.

Methods and Results— When transgenic mice with green fluorescent protein (GFP) expressed downstream of the Tie2 promoter were injected with Ac-LDL, Ac-LDL was specifically endocytosed by sinusoids, and Tie2 expression was more pronounced in the arteries, arterioles, and transitional capillaries. Combining these 2 functional endothelial markers and using confocal microscopy to obtain 3-dimensional images, we identified transitional zones where arterioles emptied into the sinusoids. Alternatively, coinjection of lectin with DiI-Ac-LDL has a similar result in normal mice, as seen in Tie2/GFP mice, and can be used to differentiate vessel types in nontransgenic mice.

Conclusions— These results demonstrate that bone marrow vasculature is functionally heterogeneous. Methods to study changes in the marrow vasculature using microvascular density or quantifying changes in the vascular niche need to take this heterogeneity into account.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 1843-1844. [Extract] [Full Text]