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Chapter 123 The Blood Vessel Wall 1851

Endothelium

P2Y TM Heparan SO T
EPCR 4 P
F
CD39 5’-Nuc Thrombin AT I
ATP AMP Adenosine PC aPC t-PA–PAI-1
Anti-thrombogenic ADP
PS IIa
Xa
IIa
PGI ,NO Va VIIIa XIa IXa VIIa TF
2
Xa
Platelet aggregation Coagulation
Prothrombin Thrombin Fibrinolysis
Prothrombogenic
vWF IX IXa X Xa
Villa
TF

Fig. 123.2 OVERVIEW OF ENDOTHELIAL FUNCTION IN COAGULATION. ADP, Adenosine
diphosphate; AMP, adenosine monophosphate; AT, antithrombin; ATP, adenosine triphosphate;
EPCR, endothelial protein C receptor; 5′-Nuc, ecto-5′-nucleotidase; NO, nitric oxide; P2Y, purinergic receptor
1; PAI-1, plasminogen activator inhibitor 1; PC, protein C; PGI 2 , prostaglandin I 2 (prostacyclin); PS, protein
S; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; t-PA, tissue plasminogen
activator; vWF, von Willebrand factor.

the cell. Alternatively, molecules can be moved across the cell by esized as a mechanism for increasing permeability in inflammatory
plasmalemmal vesicles or caveolae, which are abundant in capillary states. 212
endothelial cells. Caveolae are 50–100-nm membrane invaginations
that can participate in transcytosis as well as in the translocation of
glycosylphosphatidylinositol-linked proteins into the cytoplasm and The Endothelium as a Nonthrombogenic Surface
206
in transmembrane signaling. Because of the known leakiness of
tumor microvasculature, investigators have studied these microvessels The molecular mechanisms of hemostasis and thrombosis are
207
and identified a structure designated the vesiculovacuolar organelle. addressed in Chapters 115 and 116 and 118–120. This section places
These organelles are grape-like clusters of interconnecting uncoated the endothelium in the appropriate context in these processes. An
vesicles and vacuoles that span the entire thickness of vascular overview of endothelial cell contributions to the anticoagulant and
endothelium, thereby providing a potential transendothelial con- procoagulant states is shown in Fig. 123.2. Normal unperturbed
207
nection between the vascular lumen and the extravascular space. endothelium presents a nonthrombogenic surface to the circulation
Interestingly, their function is enhanced by injection into normal skin by inhibiting platelet aggregation, preventing the activation and
207
of VEGF, which is known to increase the permeability of vessels. propagation of coagulation and enhancing fibrinolysis. 213–217 These
Localization of caveolin to vesiculovacuolar organelles suggests that activities are accomplished by both passive and active processes.
this structure is a fusion of caveolae. 207 Conversely, when injured or under inflammatory conditions, the
During inflammation, binding of neutrophils to the endothelium endothelium may become procoagulant.
results in the generation of oxidants that can mediate endothelial When in close proximity to endothelial cells, platelets become
208
cell injury and increase permeability. Upon adhesion of neutro- unresponsive to agonists. This inhibition of platelet aggregation is
phils to the endothelium, leukocyte CD18 (β2 integrin)-mediated accomplished by secretion of prostacyclin (prostaglandin I2 [PGI 2 ])
signals trigger the release of the neutrophil cationic protein called and NO, and by surface expression of an ecto-adenosine phospha-
heparin-binding protein/CAP37/azurocidin, which in turn induces tase (ADPase)/CD39/nucleoside triphosphate diphosphohydrolase
formation of gaps between endothelial cells and macromolecular (NTPDase-1). 216,218 Prostacyclin is synthesized mainly by vascular
209
efflux. Thrombin, an inflammatory mediator, can increase endo- endothelial and smooth muscle cells as a product of arachidonic acid
thelial permeability by several mechanisms resulting from activation metabolism. It inhibits platelet activation, secretion, and aggregation,
of its receptor on endothelial cells. 210–212 First is an increase in as well as monocyte interactions with endothelial cells. It also causes
transcellular vesicular permeability. Second is increased paracel- vascular smooth muscle cell relaxation. NO similarly has a wide range
lular permeability that results from phosphorylation of endothelial of functions, including inhibition of platelet adhesion, activation, and
cell nonmyosin light chains and contractile activity generated by aggregation. Most of the NO released from endothelial cells is elabo-
movement of actin and myosin filaments past each other. The rated abluminally, where it acts on the smooth muscle cell to cause
contraction and retraction of endothelial cells are accompanied by vasodilation. However, some NO may enter the lumen and thereby
“loosening” of intercellular junctions and focal integrin contacts with diffuse into platelets. Prostacyclin and NO can act synergistically to
216
the ECM. Finally, thrombin may alter the repulsive effect of the reverse platelet aggregation. The released platelet agonist, ADP,
218
negatively charged glycocalyx. An increase in paracellular perme- can be inactivated by endothelial membrane-associated CD39.
ability may result from alteration of cell–cell contacts present at Metabolism of ATP and ADP to adenosine monophosphate (AMP)
tight junctions and adherens junctions secondary to posttranslational by CD39 eliminates platelet recruitment and returns platelets to their
modification of components of these junctions such as claudins resting state. Adenosine, which is generated by hydrolysis of AMP
202
and VE-cadherin. Pericyte contractility also has been hypoth- by ecto-5′-nucleotidase, acts to inhibit platelet aggregation and cause