Page 2076 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 123 The Blood Vessel Wall 1845

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venules (HEVs). The endothelial cells of these venules (HEV-ECs) development proceeds in several ways. Vasculogenesis is the process
exhibit a plump or cuboidal morphology (hence the name high endo- whereby blood vessels form de novo from the differentiation of
thelial venule), display intense biosynthetic activity, and are encircled mesodermal precursors. Angiogenesis is the outgrowth of new capil-
by a continuous thick basal lamina formed from ECM components laries from preexisting vessels and is thought to be the major mode
produced by surrounding pericyte-like cells called fibroblastic reticular of new vessel development in the adult. Arteriogenesis, or collateral
cells. HEV-ECs are composed of free ribosomes, multivesicular bodies, development, is the rapid enlargement of preexisting collateral arte-
well-developed Golgi apparatus, tissue-specific adhesion molecules, rioles after occlusion of a supply artery. Lymphangiogenesis is the
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and chemokines. They secrete a thick glycocalyx, of which a propor- development of lymphatic vessels, which are required for transporta-
tion is glycosylation-dependent cell adhesion molecule 1, a ligand for tion of extravasated lymph and lymphoid cells. Finally, in some
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L-selectin. CD34 is another HEV “addressin” on peripheral lymph neoplasms, tumor cells rather than endothelial cells form vascular
node endothelial cells. Endothelium of mesenteric lymph nodes and channels or a portion of some vessels, a process termed vasculogenic
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Peyer patches express mucosal addressin cellular adhesion molecule 1 mimicry. A similar nonendothelial cell lining of vascular channels
(MAdCAM-1) as a ligand for L-selectin and α4β7 integrin. HEV-EC can be created by placental cytotrophoblasts forming hybrid fetal–
express additional L-selectin ligands grouped together as peripheral maternal vessels in the endometrium. 71
node addressins (PNAd) including glycosylation-dependent cellular
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adhesion molecule 1 (GlyCAM-1), endomucin, and nepmu-
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cin. Expression of these different addressins may recruit specific Vasculogenesis
subpopulations of lymphocytes to different lymphoid tissues (i.e.,
they facilitate the “homing” of lymphocytes). Several other proteins, Vasculogenesis in the yolk sac proceeds initially by the differentiation
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including the chemokine receptor DARC (Duffy antigen receptor for of mesodermal cells into angioblasts. Angioblasts are vascular cells
chemokines) and the antiadhesive matrix protein Hevin, have been that express some, but not all, endothelial markers. These cells arise
identified as being preferentially expressed by the high endothelial from mesodermal cells resting on the endoderm (splanchnopleuric
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venule. Tight junctions are present at intermittent spots, and mesoderm) but not from the mesoderm adjacent to the ectoderm
extensive overlap between the membranes of adjacent cells prevents (somatopleuric mesoderm). Thus it is believed that whereas the
macromolecules from interendothelial transit. However, when lym- endoderm positively regulates vascular development, the ectoderm
phoid cells transit to the high endothelial venule, there is a temporary negatively regulates vasculogenesis. Organs that are primarily of
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breach in the barrier. Evidence suggests that the high endothelial ectodermal origin (e.g., brain and kidney) are vascularized by angio-
venule not only plays a critical role in homing and recruitment of genesis and not by vasculogenesis. The mesodermal cells migrating
immune cells, but also can influence the outcome of the immune outward from the endoderm form primitive structures termed blood
response. 63 islands. Whereas the cells at the center of the blood island are hema-
topoietic precursors, those arranged peripherally are angioblastic
precursors. Vasculogenesis within the embryo begins shortly after that
Bone Marrow Sinuses in the yolk sac, again in close association with endoderm. However,
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except for a region on the ventral aspect of the embryonic aorta,
Much less is known about the bone marrow (BM) sinuses than about intraembryonic vascular development occurs in solitary angioblasts
the high endothelial venule. The BM sinus endothelial cell is flat, in rather than blood islands. Angioblasts differentiate in situ and form
contrast to that of the high endothelial venule, with loose interdigi- primary capillary plexuses with lumens, or they migrate and fuse with
tated junctions and the basal lamina is discontinuous. It has been other angioblasts or capillaries. Fusion of angioblasts or blood islands
suggested that hematopoietic cells traverse pores present at attenuated results in the formation of a capillary plexus that undergoes extensive
areas of the endothelium rather than move by an interendothelial remodeling over the developmental period. 72
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route. Clearly, the BM sinus endothelial cell is specialized given the
regulated egress of cells from the BM. For example, if a red blood
cell (RBC) that still is nucleated begins to enter the circulation, the Vasculogenesis in the Adult
body of the cell is allowed to cross and is released as a reticulocyte,
while the nucleus is retained extravascularly. The adventitial reticular Although initially said to occur primarily in the embryo, vasculo-
cell (similar to a pericyte) is also thought to play an important role genesis may also play a role in promoting vascular development in
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in controlling hematopoietic cell egress. Stromal cell–derived factor adults. The identification of circulating BM-derived vascular precur-
1 (SDF-1; also called CXC-chemokine ligand [CXCL]12) and che- sors and the demonstration that these precursors can integrate into
mokine receptor CXC-chemokine receptor (CXCR)4 interactions are the vasculature at sites of angiogenesis describe an adult form of de
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essential for stem cell homing, mobilization, and transendothelial novo vessel development. Two distinct BM-derived precursors with
migration into the BM. 66,67 SDF-1 activates the integrins lymphocyte the ability to differentiate into vascular cells have been identified: (1)
function-associated antigen 1 (LFA-1 [αLβ2]), very late antigen 4 accumulating evidence points to a single precursor, the hemangio-
(VLA-4 [α4β1]), and very late antigen 5 (VLA-5 [α5β1]). Whereas blast, which can differentiate into either hematopoietic or endothelial
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vascular cell adhesion molecule 1 (VCAM-1), which is expressed on cells, and (2) a multipotent nonhematopoietic adult progenitor
BM endothelial cells (and spleen endothelial cells in the mouse), cell, which is thought to represent a BM mesenchymal stem cell
appears to be the major BM addressin for hematopoietic progenitor (BM-MSC). When injected intravenously into adult mice, these
cells expressing VLA-4, intercellular adhesion molecule 1 (ICAM-1) MSCs differentiate into vascular cells, hematopoietic cells, and several
binds LFA-1. 67,68 Endothelial selectins also have been implicated in epithelial cell types. 76,77 Once seeded on a synthetic graft, BM-MSCs
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promoting hematopoietic stem and progenitor cell homing to the differentiate into both smooth muscle and endothelial cells in vivo.
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BM. Factors such as CD44, cytoskeletal rearrangement, and matrix Both types of multipotential precursor populations express CD133, a
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metalloproteinases (MMPs) are other key players in the homing cell surface marker that is lost upon further maturation. However,
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process related to the endothelium. The BM endothelium is also only the hemangioblast expresses CD34. Whether MSCs are able to
involved in regulating hematopoiesis (see Relationship Between circulate and thus contribute to neovascularization outside the BM
Vascular Development and Hematopoiesis section). remains to be shown. Various stresses, including neoplasia, sepsis,
burns, and trauma, have been suggested to induce mobilization of
BM-derived endothelial precursors, which express CD133, CD34,
VASCULAR DEVELOPMENT AND DIFFERENTIATION and VEGFR-2. Cytokines that reportedly induce mobilization of
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BM-derived endothelial precursors include VEGF-A and granulocyte
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The human embryo develops a vascular system by the third week, macrophage colony-stimulating factor (GM-CSF), as well as SDF-1,
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when its nutritional needs are no longer met by diffusion. Vascular which stimulates mobilization of CXCR4+ BM cells, including