Page 2075 - Hematology_ Basic Principles and Practice ( PDFDrive )

1844 Part XII Hemostasis and Thrombosis

manifested by the asymmetric distribution of cell surface glycopro- composition of the subendothelium varies with location in the vascular
teins and by the unidirectional secretion of some ECM proteins and tree, age, and disease states. 2,14,40 Endothelial cells bind to the ECM via
chemical mediators. 28,29 Although in cultured endothelial cells an heterodimeric cell surface glycoproteins—the integrins—which link
apical–basal polarity is established before confluence, intercellular and integrate matrix proteins to the cytoskeleton at sites referred to as
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junctions may have a role in maintaining the asymmetry in vivo. 28,30 focal contacts. The integrins detected in resting endothelium include
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Four types of intercellular junctions between adjacent endothelial α6β1, α5β1, α2β1, and αvβ3. Interestingly, endothelial cells express
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cells have been described 30,31 : tight junctions, gap junctions, adherens integrins on luminal as well as abluminal surfaces. The ECM serves
junctions, and syndesmos. Their distribution varies along the vascular several important functions: (1) it serves as a barrier to macromolecules
tree, with tight junctions occurring more frequently in the larger in the event of disruption of the endothelium; (2) it sequesters growth
arteries and brain vasculature, correlating with a more stringent factors and mediates their high-affinity binding to endothelial cells
requirement for permeability control. The molecular structure of (e.g., heparan sulfate binds to fibroblast growth factor [FGF]); and (3)
endothelial tight junctions is similar to that of epithelial cells, consist- it acts as a counterstructure for the binding of endothelial cell integ-
ing of a network of fibrils, with the integral membrane components rins. 14,40,43 This binding of endothelial cells to the ECM serves at least
composed of occludin, claudin-5, and junctional adhesion molecules four purposes: (1) Whereas certain matrix molecules provide a physical
(JAMs), which associate with various structural and signaling proteins scaffold, others act as haptotactic agents, inducing endothelial cells to
14
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on the cytoplasmic face. The distribution of gap junctions tends to migrate. (2) Clustering of integrins at focal adhesion contacts by
follow that of tight junctions. Connexin 37, connexin 40, and con- certain matrix molecules can transduce survival or differentiation
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nexin 43 are gap junction proteins that have been detected in signals by causing phosphorylation of various proteins and lipids.
endothelial cells. Gap junctions mediate communication between Whereas fibronectin and vitronectin provide survival signals, laminins
adjacent endothelial cells, and between endothelial cells and pericytes appear to signal differentiation. 44–46 (3) By maintaining cell shape,
or smooth muscle cells; they also contribute to the endothelial barrier integrin-mediated cell spreading provides an antiapoptotic signal
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and vascular integrity. Adherens junctions are formed by transmem- independent of direct integrin-initiated signal transduction. (4) By
brane glycoproteins called cadherins, which make the link between anchoring the cell, the matrix provides a mechanism whereby blood
cell-to-cell contacts and the cytoskeleton. Several different types of flow at the luminal surface of the endothelium creates shear stress,
cadherins are expressed in endothelial cells. The endothelial-specific which also transmits signals to cells. 37
cadherin vascular endothelial cadherin (VE-cadherin [cadherin-5]) is
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expressed on virtually all types of endothelium. Similar to other
cadherins, VE-cadherin forms homotypic contacts with VE-cadherin Endothelial Heterogeneity
on adjacent cells. Within the cell, VE-cadherin complexes with
catenins, which, through other proteins, contact the actin cytoskel- Despite their common features, quiescent endothelial cells in vivo
eton. Homotypic engagement of VE-cadherin results in density- represent a widely heterogeneous population, with their phenotype
dependent inhibition of endothelial proliferation, which appears to depending on vessel caliber and location. Exposure to different physical
be mediated by association of vascular endothelial growth factor forces (e.g., arteries vs. veins) and the different functions served by
receptor 2 (VEGFR-2) with VE-cadherin, thereby sequestering vessels of different caliber are reflected in different endothelial pheno-
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VEGFR-2 at the membrane and preventing its internalization into types. However, study of the molecular basis of the heterogeneity of
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signaling compartments. The structure of the fourth type of junc- these different populations is just beginning. Experiments using serial
tion, the syndesmos, is not well elucidated. analysis of gene expression and in vivo delivery of phage display peptide
Other membrane proteins that are located at interendothelial libraries have revealed organ- and tumor vasculature–specific molecules
junctions include platelet endothelial cell adhesion molecule 1 that will help to elucidate the molecular basis of endothelial
(PECAM-1), which may be important in directing the formation of heterogeneity. 49–51 Within the microvasculature is a structural hetero-
junctions, nectins, JAMs, endothelial cell-selective adhesion molecule geneity of capillaries, depending on the organ supplied. Even within a
(ESAM), and the integrins (particularly α2β1 and α5β1). 34,35 In single organ, endothelial cells exhibit different phenotypes, depending
addition to the functions listed previously, intercellular contacts are on their functional role. When microvessels from different organs are
important in maintaining cell survival. 36 harvested and cultured in vitro, they lose some of their distinctive
On the luminal side, endothelium is exposed to blood elements characteristics with progressive passaging. Some specialization of the
and, under pathologic conditions, to circulating molecules such as different endothelial cells can be retained if they are cocultured with
cytokines and bacterial products. Engagement of endothelial recep- cells or matrix from the organ from which they are derived. Thus
tors by these humoral factors activates a well-described series of matrix proteins, soluble factors from the organ, or heterotypic contacts
responses, including the recruitment and transmigration of leukocytes with parenchymal cells or pericyte or smooth muscle cells are believed
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and changes in endothelial cell coagulant activity (see The Endothe- to be important factors in specifying endothelial cell phenotype.
lium as a Nonthrombogenic Surface section). Biomechanical forces Conversely, emerging evidence indicates that endothelial cells in turn
resulting from pulsatile blood flow have been shown to mediate provide instructive morphogenic cues during organogenesis and in
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striking changes in endothelial morphology and metabolism. Vessels adults. Specific examples of microvessels found in hematopoietic
must withstand three types of physical forces: radial distension tissues are discussed in the following sections. Endothelial cells from
(tension), longitudinal stretch, and tangential shear stress. In response veins and arteries and from capillaries of different organs demonstrate
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to flow (shear stress), endothelial cells reorganize their cytoskeletal heterogeneity at structural, functional, and molecular levels. Intrigu-
architecture, rearrange focal contacts at the basal surface, and align ingly, phenotypic heterogeneity also exists between neighboring
in the direction of flow. 37–39 Some endothelial cell responses following endothelial cells exposed to the same extracellular environment. In the
exposure to physical forces occur within seconds, such as activation case of endothelial-restricted vWF expression, heterogeneity denoted
of potassium channels and increased release of nitric oxide (NO), by mosaic vWF expression proved dynamically regulated by bistable
resulting in vasodilation. Other endothelial cell responses to flow are transitions in the DNA methylation status of the vWF promoter,
related to changes in gene expression and occur after a delay of a few suggesting novel stochastic phenotype switching potentials in endothe-
hours. Elements in the promoters of various adhesion molecule and lial microenvironments. 55
growth factor genes have been shown to contain sequences that
respond to shear stress (in a positive or negative fashion) and have
been referred to as the shear stress response element. 37–39 High Endothelial Venules
Endothelial cells vectorially secrete certain ECM proteins to the
abluminal face. The matrix molecules that are secreted by endothelium Lymphocyte migration into secondary lymphoid sites, such as lymph
include several types of collagen, elastin, fibronectin, laminins, and nodes, Peyer patches, and chronically inflamed nonlymphoid tissues,
proteoglycans (e.g., heparan sulfate and dermatan sulfate). The exact occurs at specialized postcapillary venules called high endothelial