Page 2077 - Hematology_ Basic Principles and Practice ( PDFDrive )

1846 Part XII Hemostasis and Thrombosis

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hematopoietic stem cells (HSCs) and EPCs. 80,81 Recent data have with pericytes develop microaneurysms. In embryos, periendothelial
implicated IL-8 as a regulator in mobilizing EPCs into the peripheral cells are thought to be derived from locally available mesenchymal
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circulation by binding both CXCR1 and CXCR2. The contribution cells as endothelial cells invade organ rudiments. Local derivation of
of BM-derived vascular precursors to angiogenic vessels in tumors periendothelial cells may be one mechanism that allows for tissue-
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is highly variable, depending on the study, the model used, and the specific phenotype of the vasculature. Evidence suggests that
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tumor cell type used. The degree of endothelial precursor incorpora- embryonic endothelial cells may transdifferentiate into vascular
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tion into the angiogenic vasculature is highly controversial; several smooth muscle cells. Evidence also indicates that some periendo-
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groups suggest negligible, if any, involvement by distant precursors. thelial cells are derived from the neural crest during embryogenesis
The problem arises in part from the poor definition of a circulating and from BM-derived precursors in adults. 94–97 Although some
endothelial precursor cell. Many, if not all, of the markers used to studies have shown pericytes to be potential antivascular targets for
define this rare cell population are shared with hematopoietic stem tumor therapy, 96,98 other work has suggested that pericytes act to limit
or progenitor cells, and the distinction between the endothelial and tumor metastasis. 99
hematopoietic precursor has not been rigorously addressed in the
majority of studies. More recent work has suggested that BM-derived,
perivascular CD11b+ hematopoietic cells secreting angiogenic cyto- Extracellular Matrix
kines have been misidentified as endothelial precursor cells. 84,85
It is thought that whereas interstitial collagens (e.g., collagen I) and
provisional plasma-derived fibronectin–fibrin matrices stimulate
Angiogenesis endothelial tubular morphogenic events, laminin-rich matrices lead
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to endothelial differentiation and stabilization events. Mice deficient
In a normal adult, angiogenesis occurs primarily in the female in fibronectin die during embryogenesis and show vascular defects.
reproductive system. However, angiogenesis is a process that has a Type I collagen-deficient mice die of circulatory failure just before
major impact in several pathologic situations. Probably the best birth. Although most tumor vessels are covered by basement mem-
known and studied example of pathologic neovascularization occurs brane, this layer has multiple structural abnormalities consistent with
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during tumor progression. Angiogenesis also is important in chronic ongoing vascular activation in tumors. ECM proteins or their
inflammation, ischemia, and wound healing. proteolytic fragments have been shown to inhibit angiogenesis.
Capillary sprouts from the existing microvasculature form second- Dissolution of the underlying matrix by MMPs and heparanases
ary to an inciting stimulus that results in increased vascular permeabil- allows endothelial cells to migrate at the initiation of angiogene-
ity, accumulation of extravascular fibrin, and local proteolytic sis. 101,102 Matrix-bound growth factors are also released as a conse-
degradation of the basement membrane. 86–88 Endothelial cells overly- quence of ECM degradation. The balance between positive and
ing the disrupted region become “activated,” change shape, and negative regulators is the basis of tight control in this process. Tissue
extend elongated processes into the surrounding tissue. Filopodia plasminogen activator (t-PA) and urokinase plasminogen activator
extending from the specialized endothelial cells at the tip of the (u-PA), by generating plasmin, can activate collagenases and other
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vascular sprout guide the migration of the nascent vessel. Directed MMPs. Plasminogen activator inhibitors (PAIs) may block angiogen-
migration toward the angiogenic stimulation results in the formation esis at this step. Action of the MMPs is required for angiogenesis, and
of a column of endothelial cells. Just proximal to the migrating tip the tissue inhibitors of MMPs regulate their function. 103
of the column is a region of proliferating endothelial cells. These
proliferating cells cause an increase in the length of the sprout. In the
region of proliferation, up to 20% of endothelial cells may enter the Cell Adhesion Molecules
cell cycle. This is in marked contrast to quiescent endothelium, of
which less than 0.01% of cells are cycling. Proximal to the prolifera- Of the various classes of cell adhesion molecules involved in angio-
tive zone, the endothelial cells undergo another shape change, adhere genesis, the integrins have been the most studied. 14,104,105 Although
tightly to each other, and begin to form a lumen. Evidence suggests it is universally accepted that integrins and integrin ligands function
that endothelial lumina arise through the formation and fusion of in angiogenesis, their exact actions remain unclear. In particular,
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intracellular vacuoles. Secondary sprouting from the migrating tip substantial controversy surrounds the role of αvβ3 integrin. 14,104,106
results in a capillary plexus, and fusion of individual sprouts at their Immunohistochemical studies localize this integrin to the tips of
tips closes the loop and circulates blood into the vascularized area. sprouting vessels. Neutralizing antibodies abrogate angiogenesis and
Activated macrophages and platelets, by secreting growth factors, induce vascular cell apoptosis in vivo, and inhibitory peptides or pep-
cytokines, proteases, and protease inhibitors, can influence all phases tidomimetics blocking adhesive functions of integrin αvβ3 inhibit
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of the angiogenic process. 91 angiogenesis in a variety of animal models. However, mice lacking
The morphologic features described are characteristic of sprouting αv show extensive angiogenesis, and mice and humans (Glanzmann
angiogenesis. Another mechanism of angiogenesis, “intussusceptive thrombasthenia) lacking β3 integrin also show normal angiogenesis.
microvascular growth,” refers to vascular network formation by inser- Notwithstanding the discrepancies outlined, preclinical studies have
tion of interstitial tissue columns, called tissue pillars or posts, into validated αvβ3 and potentially other integrins (αvβ5, α1β1, α2β1,
existing vascular lumen and subsequent growth of these columns, α5β1, α6β4) as therapeutic antiangiogenic targets, and clinical
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resulting in partitioning of the vessel lumen. Periendothelial cells, trials with combination therapy are currently in progress. One of
including pericytes and myofibroblasts, which invade the pillar core the integrin receptors for fibronectin, α5β1, has been shown to be
stabilize the structure in association with collagen fibrils. The mecha- necessary for vascular development, and α2β1 seems important for
nisms of intussusceptive angiogenesis are less well described, but the formation of tubes by endothelial cells in vitro. However, there
hemodynamic factors appear to be involved. 92 likely is a dynamic regulation of β1 integrins during angiogenesis
because constitutive activation of this integrin inhibits endothelial
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sprouting in vitro and angiogenesis in vivo. The junctional proteins
Recruitment of Periendothelial Cells VE-cadherin and PECAM-1, and possibly JAM-1, are expressed early
in development and have a role in assembling the vasculature. 33,110,111
Whether formed by vasculogenesis or angiogenesis, maturation of
new vessels requires recruitment of smooth muscle cells or pericytes
to reestablish vessel integrity. Periendothelial cells provide structural Guidance Molecules
support, assist in production of the ECM, provide contractile func-
tion so as to modulate vessel caliber, and maintain the cells in a Similar to the nervous system, the vascular system forms a highly
quiescent state. Genetically altered mice that fail to invest their vessels ordered, branching network. The ordering of this patterned network