Page 1998 - Williams Hematology ( PDFDrive )

1972 Part XII: Hemostasis and Thrombosis Chapter 115: Vascular Function In Hemostasis 1973

muscles cells, and macrophages, which express plasminogen activators, In vivo, the circulating half-life of t-PA is approximately 5 min-
plasminogen activator inhibitors, and fibrinolytic receptors. utes. Infusion of DDAVP, bradykinin, platelet-activating factor (PAF),
endothelin, or thrombin is associated with an acute release of t-PA,
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ENDOTHELIAL CELL PRODUCTION OF and a burst of fibrinolytic activity can be detected within minutes. In
FIBRINOLYTIC PROTEINS the mouse lung, exposure to hyperoxia leads to 4.5-fold upregulation
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of t-PA mRNA in small-vessel endothelial cells. In humans, infusion
In 1958, Todd demonstrated that human blood vessels possess fibrino- of TNF into patients with malignancy is associated with an increase in
lytic activity that is dependent upon an intact endothelium. 102,103 We plasma t-PA. Deficient release of t-PA in response to venous occlusion
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now know that the endothelium is the principal source of t-PA in vivo in humans is associated with deep venous thrombosis, as well as atro-
where it appears to be highly restricted to small blood vessels in specific phie blanche and other cutaneous vasculitides. 125
anatomic locations, a pattern that likely reflects the heterogeneity of In vivo, urokinase plasminogen activator (u-PA) is not a product
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endothelial cells as they respond to a myriad of tissue-specific cues. 104,105 of resting endothelium, but is produced primarily by renal tubular
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In the baboon, for example, sites of t-PA production include 7 to 30 μm epithelium. Expression of u-PA mRNA in endothelium, however, is
precapillary arterioles and postcapillary venules, but not large arteries strongly stimulated during wound repair and physiologic angiogenesis
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and veins. In the mouse lung, similarly, bronchial, but not pulmonary, within ovarian follicles, corpus luteum, and maternal decidua. Endo-
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endothelial cells express t-PA. Moreover, enhanced expression of t-PA thelial cells passaged in culture do synthesize u-PA, and expression of
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at branch points of pulmonary blood vessels may reflect stimulation by its mRNA is stimulated by TNF-α by 5- to 30-fold. Small increases in
laminar shear stress. In addition, peripheral sympathetic neurons that u-PA have also been observed in vitro in response to IL-1 and LPS. 131–133
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invest the walls of small arteries may represent a significant source of The association of u-PA with the blood vessel wall appears to reflect
circulating t-PA. 109 its association with the u-PA receptor (uPAR) which may fulfill a variety
Although in vitro studies suggest that t-PA expression in cultured of nonproteolytic functions ranging from directed cell migration to cel-
endothelial cells is regulated by a wide array of factors, only a few of these lular adhesion, differentiation, and proliferation (Fig. 115–6). In the
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pathways have been confirmed in vivo. Thrombin, histamine, 111,112 adult mouse, uPAR mRNA is not normally detected by in situ hybrid-
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113
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oxygen radicals, phorbol myristate acetate, DDAVP (deamino ization in the endothelium of either large or small blood vessels.
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D-arginine vasopressin), and butyric acid liberated from dibutyryl However, upon stimulation with endotoxin, expression is detected in
cAMP all increase t-PA mRNA in cultured endothelial cells. Both endothelium lining aorta, as well as arteries, veins, and capillaries in
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thrombin and histamine appear to act via receptor-mediated activation heart, kidney, brain, and liver, and in renal tubular epithelial cells. 127
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of the protein kinase C pathway. Laminar shear stress stimulates both Plasminogen activator inhibitor (PAI)-1 is likely to function as a
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t-PA secretion and steady-state mRNA levels. Hyperosmotic stress major regulator of plasmin generation in the vicinity of the endothelial
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and repetitive stretch also enhance t-PA expression. 119,120 In addition, cell. Thrombin, IL-1, transforming growth factor β, TNF, lipoprotein(a)
differentiating agents, such as retinoids, 121,122 stimulate transcription of (Lp[a]), and LPS all induce dramatic increases in steady state PAI-1
t-PA in endothelial cells in vitro. message levels. 110,131,132,136,137 Heparin-binding growth factor 1 reduces
Plasmin
t-PA t-PA
A-tail A-tail
PLG PLG
u-PA
A 2
A 1 A 2 A 3 A 4 A 1 A 2 A 3 A 4 U 1

p11 p11 uPAR
U
U 3 2

A Plasma membrane B Plasma membrane

Figure 115–6. Schematic of principal endothelial cell fibrinolytic receptors. A. The annexin A2/S100A10 heterotetrameric complex. Annexin A2
consists of a hydrophilic aminoterminal tail domain (A-Tail, approximately 3 kDa), and a membrane-oriented carboxyl terminal core domain (approxi-
mately 33 kDa). 311,312 The tail domain contains residues required for tissue-type plasminogen activator (t-PA) binding. The core domain is composed of
four homologous annexin repeats (A1, A2, A3, and A4), each consisting of five α-helical regions that contribute to calcium-dependent phospholipid
binding sites. Repeat 2 appears to be most important for the interaction of annexin A2 with the endothelial cell surface. Plasminogen (PLG) binding
requires lysine residue 307 within helix C of repeat 4. B. Urokinase plasminogen activator receptor (uPAR) is a 55- to 60-kDa, glycosylphosphatidyli-
nositol-linked protein that consists of three disulfide-linked domains (U1, U2, U3). Domain 1 contains sequences required for urokinase plasmino-
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gen activator (u-PA) binding, while domains 2 and 3 mediate the receptor’s interaction with matrix proteins such as vitronectin. Domain 3 contains
glycosylphosphatidylinositol-linked membrane anchor. (A, adapted with permission from Gerke V, Creutz CE, Moss SE: Annexins: linking Ca2+ signalling to
membrane dynamics. Nat Rev Mol Cell Biol 6(6):449–461.)

Kaushansky_chapter 115_p1967-1984.indd 1973 9/18/15 10:08 AM