Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 549

the absence of antithrombin-3 (AT3). 127 It inhibits both clotting factor-Xa and the
complex made of tissue factor and clotting factor-VIIa by rapid formation of TFPI-
FXa complex, a potent inhibitor of the TF-VIIa complex [ 1006 ].
Antithrombin-3 is a major plasma inhibitor of FXa. Antithrombin-3 also in-
hibits thrombin and FIXa. Endothelial cells inhibit platelet aggregation, releasing
inhibitors such as prostacyclins (PGI2) and nitric oxide. 128
serpin-E1 129 inhibits urokinase, thrombin, and plasmin. It is mainly produced
by endothelial cells. It is also secreted by other cell types, particularly adipocytes.
It resembles antithrombin-3, but at and near the cell surface. It inhibits serine
peptidases tissue- (tPA) and urokinase-type (uPA) plasminogen activators that
activate plasminogen, hence impeding fibrinolysis (Sect. 9.8.2 ).
Endothelial cells activate fibrinolysis by binding plasminogen activator inhibitor
PAI1. Serpin-E1 and -F2 130 are plasma enzymes that bind to fibrin and inhibit
fibrinolysis. Serpin-F2 also deactivates plasmin.
Blood can be exposed to clotting stimuli without initiating coagulation. Clotting
is initiated on loci larger than a threshold size in the absence of fluid flow [ 1007 ].
The magnitude of the threshold size can be described by the Damk ohler number ,
which measures competition of reaction and diffusion. 131 Reaction produces activa-
tors at the site, and diffusion removes activators from the site.
Cytokines such as tumor-necrosis factor- (TNFSF1) influence the expression

of genes in endothelial cells that produce anti- and prothrombotic agents, such
as plasminogen activator inhibitor PAI1, tissue- (tPA) and urokinase-type (uPA)
plasminogen activators, thrombomodulin, nitric oxide synthase NOS3, and vascular
cell adhesion molecule VCAM1.
Endothelial cells that coat large blood vessel lumen are permanently exposed to
blood flow-induced pulsatile shear and tensile stress on their apical and basolateral
surface, respectively. Interplay between cytokines and hemodynamic stress field can
modify the sensitivity of endothelial cells to inflammatory cues.
The response of endothelial cells to TNFSF1 is modulated by shear rather than
tensile stress [ 1009 ]. Mechanotransduction and TNFSF1 additively promote PAI1
production, but reduce cytokine effect on VCAM1, as well as impede that on tPA
and uPA synthesis. These effects rely on mitogen-activated protein kinase modules
as well as NF

α

κ B and AP1 transcription factors.

127 Factor-Xa is an activator of the TF-FVII complex that is blocked by AT3 in the presence of
heparin [ 1005 ].
128 Prostacyclin release from endothelial cells is enhanced when they are subjected to pulsatile flow
compared with steady flow.
129 Clade-E, member-1 serine peptidase inhibitor is also named peptidase-nexin and type-1
plasminogen activator inhibitor (PAI1). Plasminogen activator inhibitor-2 (PAI2) is secreted by
the placenta.
130 A.k.a.

2PI), and plasmin inhibitor (PlI).
131 The Damk ohler number, a measure of the rate of reaction of a molecule relative to diffusion, is
also called the Thiele modulus. The Biot number is a measure of the rate of external transfer of a
substance with respect to the diffusion rate.

α 2-antiplasmin ( α 2AP), α 2-plasmin inhibitor ( α