CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization.
BACKGROUND
Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis.


RESULTS
CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44-/- mice (wild-type, 54.5+/-14.9% versus CD44-/-, 24.1+/-9.2%, P<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29+/-12% versus CD44-/-, 18+/-7% CD11b-positive cells/square, P<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764+/-572 versus good collateralization, 2817+/-1029 AU, P<0.05).


CONCLUSIONS
For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.
van Royen
N
N
Department of Cardiology, Room B2-114, Academic Medical Center, University of Amsterdam, Meibergdreef 9 1105 AZ, Amsterdam, The Netherlands. n.vanroyen@amc.uva.nl
Voskuil
M
M
Hoefer
I
I
Jost
M
M
de Graaf
S
S
Hedwig
F
F
Andert
J-P
JP
Wormhoudt
T A M
TA
Hua
J
J
Hartmann
S
S
Bode
C
C
Buschmann
I
I
Schaper
W
W
van der Neut
R
R
Piek
J J
JJ
Pals
S T
ST
D000368:Aged; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003097:Collateral Circulation / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005263:Femoral Artery; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007511:Ischemia / Q000503:physiopathology; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms
D018960:Hyaluronan Receptors; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2