Sphingosine-1-phosphate receptor 3 promotes neointimal hyperplasia in mouse iliac-femoral arteries.
OBJECTIVE
The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia.


RESULTS
A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries. Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more.


CONCLUSIONS
In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.
Department of Pathology, University of Washington, Seattle, 98109, USA.
Takuya
T
Shimizu
Allison
A
De Wispelaere
Martin
M
Winkler
Travis
T
D'Souza
Jacob
J
Caylor
Lihua
L
Chen
Frank
F
Dastvan
Jessie
J
Deou
Aesim
A
Cho
Axel
A
Larena-Avellaneda
Michael
M
Reidy
Guenter
G
Daum
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005263:Femoral Artery / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007083:Iliac Artery / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins; D013110:Sphingosine