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C H A P T E R 15

VASCULAR GROWTH IN HEALTH AND DISEASE

Janusz Rak

HEMOSTATIC, HEMATOPOIETIC, AND VASCULAR remodeling and in cancer). Structural changes leading to enlarge-
SYSTEMS AS A FUNCTIONAL CONTINUUM ment or shrinkage of such structures are referred to as vascular
remodeling. 2
Although specific demands of practice, concepts, and methodolo-
gies define the unique scope of current hematology, the underlying
biologic processes do not occur in isolation. Thus it is increasingly Cells Involved in Vascular Growth
obvious that diseases affecting bone marrow and peripheral blood
1
are closely intertwined with the state of the vascular system, which Specialized endothelial cells (ECs) constitute the crucial structural
2
acts as a niche, conduit, and regulator of many of these events. This and functional element of the adult vasculature. ECs create anti-
is exemplified by the anatomic proximity and interactions among thrombotic luminal surfaces within all blood vessels, produce an
several related cellular populations, including hematopoietic progeni- active interface between the blood and the surrounding tissues,
tors, their derivatives, endothelial cells and their precursors, platelets, control the transmural flux of fluids and macromolecules (perme-
perivascular tissues, and other components involved in blood vessel ability), and are the key component of vascular growth processes (see
2,3
formation, repair, homeostasis, and patency. The remarkable recent Chapters 122 and 123). Such growth not only involves cessation of
progress in understanding the molecular mechanisms involved in the quiescent state in subsets of resident endothelial cells, but is also
communication between these cells increasingly informs medical associated with multiple systemic events, such as release of cytokines
practice and drug discovery efforts. 2,4,5 For instance, agents designed into the circulation and mobilization of cells from the bone marrow,
to block vascular growth (antiangiogenics) in solid tumors also elicit including endothelial progenitor cells (EPCs), hematopoietic stem
6
2
hematologic perturbations, and are being considered for treatment cells (HSCs), and myeloid (bone marrow-derived) cells (BMDCs).
7
of hematopoietic malignancies. Indeed, hematopoietic, hemostatic, These cells serve as surveillance and regulatory mechanisms that
and vascular compartments can be viewed as a functional continuum, control and coordinate the responses of the peripheral vasculature
13
both in health and in disease. (Fig. 15.1). In established blood vessels the functionality of the
endothelial tube is dependent on the support of the abluminal base-
ment membrane, which is shared between these cells and one or
CONSTITUENTS OF THE VASCULAR SYSTEM more layers of contractile mesenchymal cells of the blood vessel wall
(mural cells). Among those cells, sparse networks of pericytes (PCs)
The hematopoietic and vascular systems emerge from a common are associated with capillary endothelium, while continuous sheaths
progenitor cell (hemangioblast) early during embryogenesis. Subse- of smooth muscle cells (SMCs) cover the pre- and post-capillary
2
quently, the vascular lineage evolves to form a network of channels vascular segments (arterial and venous, respectively). The thickness
that integrate, control, and reflect the structure and function of the and complexity of the vessel wall differ between veins and arteries,
8
tissues (parenchyma) and organs that they supply. Local character- and increase with vascular hierarchy, so much so that the multilay-
istics of the vascular system are superimposed on a more general, ered walls of large arteries contain their own capillary networks (vasa
hierarchical branching pattern (arborization) and arteriovenous vasorum). The growth of the vasa vasorum can be induced in and
directionality essential for the function of the circulation. Structur- contributes to the formation of atherosclerotic plaques, a process also
ally, distinct lymphatics emerge from the venous system to return involving metabolic abnormalities and increasingly well-characterized
14
extravascular (interstitial) fluid and extravasated cells to the venous molecular pathways. Blood vessel integrity and growth are also
circulation. 2 dependent on platelets and the hemostatic system (tissue factor,
Blood vessels are not only the essential supply routes of nutrients thrombin, thrombin receptor/PAR-1, the fibrinolytic system, and
and oxygen to tissues (parenchyma), but also conduits of long-range other effectors), all of which play important roles in the regulation of
2
regulatory signals (hormonal/endocrine), and an important source vascular continuity, patency, and permeability. Coagulation proteases
of paracrine cues that act on surrounding cells in a perfusion- not only regulate clot formation upon injury, but also elicit signals
independent (angiocrine) manner. 2,9,10 The latter influence may within the surrounding vascular, inflammatory, and parenchymal
constitute a regulatory niche to either stimulate or inhibit the activity cells, thereby modulating the related biologic responses and gene
of parenchymal cells, including subsets of normal and cancer stem expression patterns. 9,15
cells. 11,12 Postnatal tissue maturation imposes a quiescent phenotype
throughout the vascular system, a state that is only rarely and
transiently interrupted by posttraumatic tissue regeneration, wound Molecular Regulators of Vascular Responses
healing, vascular repair, or cyclic changes in reproductive organs.
This quiescent state may be chronically compromised in certain The state of the vascular networks is controlled by a web of intercel-
pathologies (inflammation, hyperplasia, or cancer), which can lead lular communications, which are executed by soluble growth factors,
2
to unscheduled or abnormal vascular growth. Out of several forms adhesion molecules, extracellular matrix (ECM) molecules, cell–cell
of such growth, vasculogenesis, angiogenesis, and vascular remodeling contacts, the hemostatic system, various proteases, and the intercellu-
stand out as fundamentally important and distinct. In vasculogenesis, lar exchange of molecules (proteins, mRNA, and microRNA). A part
endothelial progenitor cell self-assembly results in the formation of of this circuitry entails the emission/uptake of extracellular vesicles
new vascular channels (e.g., during embryogenesis). In contrast, (EVs), including exosomes. 2,16,17 Of the involved mediators, some are
angiogenesis is a process whereby preexisting vascular channels are essential for vascular growth and homeostasis, while others play more
extended to form additional capillary loops (e.g., during tissue pleiotropic and context-dependent roles (Table 15.1). 1,2

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