EDITORIAL FOCUS
Lysophospholipids in the regulation of endothelial barrier
function
Hazel
Lum
Department of Pharmacology, Rush Presbyterian St. Luke's Medical
Center, Chicago, Illinois 60612
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ARTICLE |
SERUM IS KNOWN TO CONTAIN heat-stable
and trypsin-sensitive bioactive factors that possess diverse biological
activities, including promotion of wound healing and tissue
regeneration as well as inflammatory processes. To date, some of these
factors are identified to be lysophospholipid ligands [i.e.,
lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P)] that
bind with high affinity to and signal through members of a subfamily of
G protein-coupled receptors encoded by the endothelial differentiation
genes (6). In addition to endothelial differentiation gene
receptors, several other biologically active phospholipids [i.e.,
platelet-activating factor (PAF), lysophosphatidylcholine
(8), and species of oxidized phosphatidylcholine
(11)] activate the PAF receptor, another lipid
ligand-specific G protein-coupled receptor (7).
Most of these lipid mediators possess potent proinflammatory properties
that directly activate the vascular endothelium. Recent work shows that
LPA and S1P activate the transcription factor nuclear factor-
B;
generate production of the cytokines monocyte chemoattractant protein-1
and interleukin-8; and upregulate expression of the adhesion molecules
vascular cell adhesion molecule-1, E-selectin, and intercellular
adhesion molecule-1 (14) as well as increase leukocyte
adhesion to the endothelial cell surface (15).
Furthermore, they are mitogenic. In particular, S1P is a potent
endothelial cell chemotactic agent, and, therefore, these lipids
are proposed to be critical regulators in wound healing
processes. PAF and other phospholipids (8, 11) that signal
through the PAF receptor are also highly proinflammatory. It is well
known that PAF increases vascular epithelial as well as endothelial
permeability, leukocyte extravasation, and promotion of cytokine
production and is implicated in several vascular diseases including
vasculitis and asthma (3, 9).
With the exception of PAF, the regulation of endothelial barrier
function by these lipid mediators is not well known. LPA and S1P appear
to promote endothelial barrier restrictiveness (1, 4, 10),
a surprising property in light of their proinflammatory and angiogenic
actions. But LPA is also shown to impair endothelial barrier function
(16, 17a), thus underscoring the incomplete understanding of the
function, regulation, and physiological role of these lipids in
vascular biology. The paper by Minnear et al. (12) in this issue of American Journal of Physiology-Lung Cellular and
Molecular Physiology adds further support to the barrier-promoting
actions of the lysophospholipids and some insight into their
physiological significance. These authors provide evidence that the
barrier-promoting effects of these lipids may account for the
permeability-decreasing activity of platelets. S1P is primarily stored
in platelets and released on cellular activation (18),
whereas LPA is released by both nonstimulated and stimulated platelets
as well as by activated fibroblasts, adipocytes, and tumor cells
(13). LPA is also found in mildly oxidized low-density
lipoprotein (17). On their generation and release, most of
these lysophospholipids are bound to serum proteins such as albumin or
lipoproteins. A key finding by Minnear et al. (12) is that
platelet-derived lipids form a complex with albumin, which then confers
barrier-promoting effects to the endothelium. The identity of the
responsible lipid(s) has yet to be determined.
An interesting finding by Minnear et al. (12) is that LPA
was not detected from the lipid-albumin complexes in one of the two
platelet batches examined despite the fact that the lipid-albumin fraction from both batches yielded potent permeability-decreasing activity. This finding strongly suggests that other lipids associated with albumin in addition to LPA play a role in the promotion of barrier
function. Furthermore, in the in vivo situation, LPA bound to albumin
is derived from multiple sources including platelets. Therefore, the
barrier-promoting property attributable to LPA from platelets is likely
to be less than that of those lipids derived predominantly from
platelets, such as S1P. Indeed, Yatomi et al. (18) found
that activated platelets released predominantly S1P, not LPA.
Furthermore, platelets in blood clots released greater amounts of SPP
than platelets stimulated with thrombin, ADP, or Ca2+
ionophores in the absence of clots (5), suggesting that
lipids secreted by platelets are stimulus selective. Thus it is clear that the lipid profile associated with albumin is critically influenced by the physiological state of platelets and, therefore, is of great
importance in the regulation of endothelial activities. However, in the
study by Minnear et al. (12), who used nonactivated platelets, the lipid composition associated with albumin varied between
the two platelet batches, indicating yet undetermined factors
responsible for the difference. Thus there is a need to fully
understand the determinants of lipid composition changes associated
with albumin, which is fundamental to our understanding of
platelet-endothelial cell biology in health and disease.
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FOOTNOTES |
Address for reprint requests and other correspondence: H. Lum,
Dept. of Pharmacology, Rush Presbyterian St. Luke's Medical Center,
2242 W. Harrison St., Suite 260, Chicago, IL 60612 (E-mail: hlum{at}rush.edu).
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