Vascular Endothelium in Inflammation 
and Metastasis 
Michael P. Bevilacqua, M.D., Ph.D. — Associate Investigator 
Dr. Bevilacqua is also Associate Professor of Pathology and a member of the division of Cellular and 
Molecular Medicine at the University of California, San Diego. He received his undergraduate degree in 
biology from the University of Pennsylvania and his M.D. and Ph.D. degrees in pathology from the State 
University of New York at Brooklyn. As a postdoctoral research fellow with Michael Gimbrone, Jr., and 
Ramzi Cotran at Brigham and Women 's Hospital and Harvard Medical School, he initiated work on 
endothelial leukocyte adhesion molecules. He continued these studies as a faculty member at Harvard 
Medical School before assuming his present position. Dr. Bevilacqua is a Pew Scholar in the Program in 
the Biomedical Sciences. 
VASCULAR endothelial cells form a cobble- 
stone-like lining of blood vessels throughout 
the body. Despite accurate predictions by certain 
investigators in the 18th century, the highly re- 
sponsive and changeable nature of vascular endo- 
thelium was not recognized until the early 
1980s. Endothelium was widely regarded as a 
"nonstick" surface that prevented blood-clotting 
and resisted the adhesion of circulating leuko- 
cytes. It is now apparent that the simple struc- 
tural features of vascular endothelium belie a 
complex functional nature. 
Our research has focused on the mechanisms 
by which the vascular endothelium can regulate 
inflammation, immunity, thrombosis, and tumor 
metastasis. It was demonstrated that soluble pro- 
tein mediators known as cytokines could act di- 
rectly on endothelial cells to increase the expres- 
sion of prothrombotic activities and promote the 
adhesion of blood leukocytes. Investigation into 
the mechanisms of leukocyte-endothelial adhe- 
sion led to the identification and characterization 
of two endothelial cell-surface glycoproteins that 
were designated endothelial leukocyte adhesion 
molecule- 1 (ELAM-1) and inducible cell adhe- 
sion molecule- 110 (INCAM-110). This discus- 
sion focuses on endothelial adhesion molecules 
and their potential roles in human disease 
processes. 
Endothelial Adhesion Molecules 
in Inflammation 
The study of inflammation has one of the 
richest histories in biomedical research. Particu- 
larly noteworthy is the work of Julius Conheim 
(1839-1884), which provided one of the first 
(and best) microscopic descriptions of the pro- 
cess. He carefully observed blood vessels after a 
local injury in transparent membranes such as the 
tongue of a frog and described the vasodilation, 
edema, and leukocyte emigration with great accu- 
racy. He also suggested that the blood vessel lin- 
ing in the area of inflammation became sticky for 
leukocytes. This concept was largely lost during 
the next century, in which a theory of leukocyte 
response to soluble mediators (chemotactic fac- 
tors) dominated. 
Until the early 1980s endothelial cells were 
thought to move politely aside or be destroyed as 
leukocytes exited blood vessels to fight bacterial 
infections or contain foreign substances. By 1985 
the view of vascular endothelium had begun to 
change. Recombinant cytokines were found to 
act directly on endothelial cells to increase dra- 
matically the adhesion of blood leukocytes, and it 
became apparent that the endothelium produces 
a "sticky" surface. By 1987 the nature of that 
surface was being elucidated, with the identifica- 
tion of two cytokine-inducible endothelial adhe- 
sion molecules designated ELAM-1 and ICAM-1 
(intracellular adhesion molecule-1). Studies on 
human tissues demonstrated that these mole- 
cules are expressed on endothelium at sites of 
inflammation. 
A solid working hypothesis emerged: foreign 
substances such as bacterial products introduced 
into tissues would stimulate local cells such as 
macrophages to synthesize and secrete cytokines. 
The cytokines would then act on vascular endo- 
thelium to promote the expression of adhesion 
molecules that would bind passing leukocytes. 
Leukocytes could then exit the blood vessel and 
migrate toward the foreign substances following 
chemotactic gradients. By 1990, through the ef- 
forts of multiple laboratories, five endothelial 
cell-surface molecules that participate in leuko- 
cyte adhesion and inflammation had been identi- 
fied, cloned, and characterized. These molecules 
fall into two families based on their structures. 
A newly described family, the vascular selec- 
tins, contains three related molecules, two of 
which can be found on endothelial cells: E- 
selectin (a new name for ELAM-1 ) and P-selectin 
(previously known as GMP-140 or PADGEM). 
The second group of endothelial leukocyte adhe- 
sion molecules are part of a much larger family 
known as the immunoglobulin superfamily. 
The pattern of expression of endothelial adhe- 
sion molecules as well as the specificity of their 
binding interactions with leukocytes contributes 
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