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158 Part II Cellular Basis of Hematology

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and bone marrow–derived cells. Cancer-related neovascularization (“angiogenic switch”). Some of these factors may upregulate VEGF in
exemplifies the diversity of processes that control cellular access to the parenchymal, stromal, and inflammatory cells, or act directly on the
perfused vascular space and the related terminology (see Fig. 15.4). endothelium. Inflammatory cells often cluster at sites of angiogenesis
Indeed, an increase in vascular density or the presence of endothelial prior to the formation of new blood vessels, where they contribute to
structures or blood within the tissue or tumor mass is not necessarily the consolidation of the proangiogenic microenvironment, or trigger
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related to angiogenesis, a process defined as the formation of new vascular growth via VEGF-dependent and independent mechanisms.
capillaries from preexisting ones (see Figs. 15.1, 15.3, and 15.4). Efficient sprouting involves metabolic reprogramming of endothelial
Instead, the vascular density and architecture represent a combination cells, including the activation of glycolysis and upregulation of phos-
of parenchymal and vascular cell responses to metabolic demands phofructokinase isoenzyme 3 (PFKFB3). 25
and regulatory circuits operative in a given context (see Fig. 15.4). VEGF plays a central and indispensable role in normal angiogenic
As mentioned earlier, these processes may include vasculogenesis, sprouting. After exposure to this potent stimulator, there is upregu-
recruitment, and assembly of undifferentiated endothelial progeni- lation of Ang2 expression in endothelial cells residing within the
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tor cells (EPCs). These cells may also mediate vascular repair in continuous monolayer of the capillary or mother vessel wall (phalanx
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response to endothelial damage (i.e., denudation) in larger vessels. cells). Endothelial Ang2 blocks tonic activation of the Tie2 receptor
Extravascular tissues may actively increase their vascular access by the constitutive presence of Ang1, and by disrupting the key
through processes of vascular cooption or intussusception, whereby mechanism maintaining capillary structure leads to the detachment
blood vessels may respectively become actively ensheathed or divided of pericytes. This is followed by local dissolution of the basement
(split) by advancing external cellular masses. Glomeruloid vessels, or membrane (by MMPs), increase in vascular permeability, and extrava-
tufts, may also increase the proximity between the parenchyma and sation of plasma proteins into the interstitium. The extravascular
the vascular space through increased capillary looping directed by deposition of fibrin and the formation of a provisional ECM provide
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forces generated by pericytes. The vascular wall may also undergo the scaffold for the formation of new capillaries. 2
different forms of physiologic and pathologic remodeling, including These processes liberate endothelial cells and initiate their direc-
circumferential lumen enlargement through growth, dilatation, or tional migration in the form of a cellular column (angiogenic sprout)
both. This is exemplified by capillary mother vessel formation prior toward the source of the angiogenic stimulus (e.g., VEGF-expressing
to the onset of proper angiogenesis (see Fig. 15.3). The vascular wall cells). Each sprout is composed of a single, specialized leading
thickening and diameter expansion, involving both endothelial and endothelial cell (tip cell) equipped with hair-like, sensing projections
mural cells, and occurring during the formation of larger “feeding (filopodia), which contain high concentrations of VEGFR2 and are
vessels” (or collaterals) upstream to tissue growth or ischemic regions, rich in other regulators (e.g., PDGF-B, SDF-1, Apelin, and Dll4). In
is often referred to as arteriogenesis or arterio/venogenesis. 18,21 Recruit- their gradient-seeking movement, tip cells are followed by a cohort
ment of pericytes to the newly assembled capillary endothelial tubes of proliferating endothelial stalk cells, which express VEGFR1 and
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signifies the process of vascular maturation or stabilization. Distinct Notch. Stronger stimulation by VEGF results in VEGFR2-dependent
mechanisms also regulate the programmed regression (pruning) of upregulation of Dll4 in tip cells, allowing them to instruct their stalk
superfluous capillaries (e.g., during vascular arborization). Moreover cell counterparts (via Notch) to retain their phenotype, refrain from
in cancer, new vascular structures are postulated to emerge as a con- independent branching, and to maintain VEGF signaling at lower
sequence of differentiation of cancer stem cells into endothelial-like levels. The latter is mediated, at least in part, by upregulation of
or pericyte-like cellular populations. 22,23 Cancer cells may also replace soluble VEGFR1, acting as a “VEGF sink.” Consequently, exogenous
endothelial cells within the capillary walls of certain tumor types, blockade of the Dll4/Notch pathway leads to excessive generation
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giving rise to a pseudoendothelial lining (vasculogenic mimicry). of tip cells and sprouts (from stalk cells), resulting in the formation
Each of these processes is driven by specialized cellular and molecular of an overly branched, hyperdense, nonperfused, and dysfunctional
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circuitry, and plays a unique role in vascular growth, homeostasis, and capillary network (“nonproductive angiogenesis”). Stimulation of
pathology, as outlined briefly below 2,4,5,24 (see Fig. 15.4). Notch receptor by the Jagged 1 ligand modulates the effects of Dll4
Vasculogenesis and vascular repair involve the recruitment of endo- on stalk cells and fine-tunes the capillary branching patterns. The
thelial precursors, such as angioblasts or EPCs, and their self-assembly, neighboring sprouts eventually connect (anastomose) to form new
differentiation, and/or structural integration within the endothelial capillary loops. This process is mediated by interaction with myeloid
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lining. Vasculogenesis is central to the origin of the vascular system cells expressing Tie-2 and NRP1 receptors. Subsequent generation
(primary capillary plexus formation) during embryogenesis prior to of the vascular lumen and resumption of blood flow occur through
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the onset of angiogenesis. Although EPC-like cells can be detected the formation of intercellular spaces between endothelial stalk cells. 2
during postnatal life, especially in the bone marrow, in walls of large Vascular maturation involves a buildup of a mural cell layer
vessels, and as circulating endothelial progenitors (CEPs) in peripheral around the newly formed endothelial tube, which is essential for
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blood, they have a more restricted role, which is mainly regulatory its functional integrity. This process entails secretion of PDGF-BB
and reparative in nature. For instance, EPCs may accumulate at sites by endothelial tip cells, which attracts regional pericytes; a source of
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of angiogenesis, but they rarely form complete vascular segments. structural support and vessel-stabilizing, pro-survival Ang1 activity.
However, EPCs may contribute to the endothelialization of denuded S1P regulates N-cadherin, which further links endothelial cells and
luminal surfaces, inner surfaces of vascular grafts, damaged lining of pericytes. Upon their attachment to the endothelial tube, pericytes
larger vessels (vascular repair), or to the recanalization of occlusive assume a more mature phenotype under the influence of transform-
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thrombi. Several molecular mechanisms control the recruitment ing growth factor beta 1 (TGFβ1). Endothelial prolyl hydroxylase
of EPCs and their retention at sites of vascular growth, including 2 (PHD2), an oxygen-sensing enzyme, also regulates pericyte
high levels of circulating VEGF, stromal-derived factor 1 (SDF-1), recruitment. These mechanisms restore vascular integrity, mechani-
expression of certain integrins, and other regulators. 2,4 cal resistance, endothelial cell survival, diminished dependence on
Angiogenesis occurs under conditions of tissue growth, wound VEGF, and restricted permeability. 2
repair, inflammation, hypoxia, or proliferative disease (e.g., cancer). Lymphangiogenesis and lymphatic dilatation represent key
The new vascular structures emerge from preexisting endothelial chan- responses of specialized lymphatic endothelial cells (LECs) to external
nels mainly through a mechanism known as sprouting angiogenesis (see stimuli. LECs express distinct molecular markers (VEGFR3, Prox-1,
Fig. 15.3). In this case, the triggering event involves the formation of LYVE-1) and respond to VEGF-C, VEGF-D, VEGF, and Ang2
a gradient of proangiogenic activity around hypoxic or activated cells. (which acts as a Tie2 agonist in LECs and a Tie2 antagonist in their
The resulting cascade of responses within the wall of the nearest capil- blood vessel counterparts—VECs). Even though LECs exhibit up
lary begins with local capillary distension to form an enlarged mother to 98% molecular similarity to VECs and originate from vascular
vessel. Although high concentrations of VEGF are sufficient to induce endothelium, they form separate networks of thin-walled vessels that
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these changes, the underlying molecular events usually involve a more serve as conduits for the collection of interstitial fluid and cells,
global shift in levels of multiple angiogenesis inhibitors and stimulators including inflammatory cells and metastatic cancer cells. 29