Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 465

cells; (2) acute vascular hyperpermeability, especially in postcapillary venules, in
response to short-term exposure to vascular permeabilizing agents such as VEGFa;
and (3) chronic vascular hyperpermeability in pathological angiogenesis.
Production of NR4a1 is regulated not only by VEGFa, but also by small
vascular permeabilizing agents, such as histamine, platelet-activating factor, and
serotonin. Unlike VEGFa that connects to VEGFR2 receptor protein Tyr kinase,
histamine, serotonin, and PAF tether to their cognate G-protein-coupled receptors.
Like VEGF, NR4a1 acts, at least partly, by increasing indirectly the NOS3 synthesis
and decreasing indirectly that of several endothelial cell junction constituents such
as cadherin-5.

9.2 Endothelium Types

9.2.1 High Endothelial Venules

High endothelial venules are specialized postcapillary venules of lymphoid tissues,
such as lymph nodes and intestine-associated Peyer's patches [ 863 ]. These venules
serve as entry of blood-convected lymphocytes into lymphoid organs. Lymphocytes
indeed migrate across high endothelial venules for immune surveillance.
High endothelial venules are lined by quasi-cuboidal (plump) endothelial cells
rather than flat, thin (except in the nucleus region) ones. These endothelial cells
allow lymphocyte extravasation into tissues, using concerted action of integrins,
selectins, and chemokines. Lymphocyte capture is initiated by L-selectin and
α 4 β 7 -integrin. Binding of CCL21 chemokine to its CCR7 receptor activates

α L β 2 -

integrin that mediates lymphocyte arrest and α 4 β 1 -integrins. Intercellular adhesion

molecule-1 and CCL21 chemokine are upregulated during fever [ 864 ].
Member ENPP2 of the ectonucleotide pyrophosphatase/phosphodiesterase
family, or autotaxin (Atx), is a secreted enzyme with lysophospholipase-D activity.
It converts lysophosphatidylcholine into lysophophatidic acid. It is released by
endothelial cells of high endothelial venules. It facilitates the entry of lymphocytes
into secondary lymphoid organs. After chemokine activation, naive lymphocytes
that search for antigens exit blood stream to lymph node by binding to autotaxin
via activated α 4 β 1 -integrin on lymphocytes. Extracellular autotaxin produces

lysophophatidic acid that enhances lymphocyte motility by binding to cognate
G-protein-coupled receptors. Lysophophatidic acid stimulates actin polymerization
in primary lymphocytes to trigger their motility [ 865 ].
In the spleen, lymphocytes exit blood stream through terminal arterioles that open
into the marginal sinus of the spleen. Autotaxin is strongly expressed in central
arterioles and spleen marginal zones.
Autotaxin also synthesizes sphingosine 1-phosphate that control lymphocyte
egress from various lymphoid tissues.