Sphingosine-1-phosphate receptor 1 regulates neointimal growth in a humanized model for restenosis
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Sphingosine-1-phosphate receptor 1 regulates neointimal growth in a humanized model for restenosis. / Braetz, Julian; Becker, Astrid; Geissen, Markus; Larena-Avellaneda, Axel; Schrepfer, Sonja; Daum, Guenter.
In: J VASC SURG, Vol. 68, No. 6S, 12.2018, p. 201S-207S.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Sphingosine-1-phosphate receptor 1 regulates neointimal growth in a humanized model for restenosis
AU - Braetz, Julian
AU - Becker, Astrid
AU - Geissen, Markus
AU - Larena-Avellaneda, Axel
AU - Schrepfer, Sonja
AU - Daum, Guenter
N1 - Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
PY - 2018/12
Y1 - 2018/12
N2 - OBJECTIVE: The main objective of this study was to define a role of sphingosine-1-phosphate receptor 1 (S1PR1) in the arterial injury response of a human artery. The hypotheses were tested that injury induces an expansion of S1PR1-positive cells and that these cells accumulate toward the lumen because they follow the sphingosine-1-phosphate gradient from arterial wall tissue (low) to plasma (high).METHODS: A humanized rat model was used in which denuded human internal mammary artery (IMA) was implanted into the position of the abdominal aorta of immunosuppressed Rowett nude rats. This injury model is characterized by medial as well as intimal hyperplasia, whereby intimal cells are of human origin. At 7, 14, and 28 days after implantation, grafts were harvested and processed for fluorescent immunostaining for S1PR1 and smooth muscle α-actin. Nuclei were stained with 4',6-diamidine-2'-phenylindole dihydrochloride. Using digitally reconstructed, complete cross sections of grafts, intimal and medial areas were measured, whereby the medial area had virtually been divided into an outer (toward adventitia) and inner (toward lumen) layer. The fraction of S1PR1-positive cells was determined in each layer by counting S1PR1-positive and S1PR1-negative cells.RESULTS: The fraction of S1PR1-postive cells in naive IMA is 58.9% ± 6.0% (mean ± standard deviation). At day 28 after implantation, 81.6% ± 4.4% of medial cells were scored S1PR1 positive (P < .01). At day 14, the ratio between S1PR1-positive and S1PR1-negative cells was significantly higher in the lumen-oriented inner layer (9.3 ± 2.1 vs 6.0 ± 1.0; P < .01). Cells appearing in the intima at day 7 and day 14 were almost all S1PR1 positive. At day 28, however, about one-third of intimal cells were scored S1PR1 negative.CONCLUSIONS: From these data, we conclude that denudation of IMA specifically induces the expansion of S1PR1-positive cells. Based on the nonrandom distribution of S1PR1-positive cells, we consider the possibility that much like lymphocytes, S1PR1-positive smooth muscle cells also use S1PR1 to recognize the sphingosine-1-phosphate gradient from tissue (low) to plasma (high) and so migrate out of the media toward the intima of the injured IMA.
AB - OBJECTIVE: The main objective of this study was to define a role of sphingosine-1-phosphate receptor 1 (S1PR1) in the arterial injury response of a human artery. The hypotheses were tested that injury induces an expansion of S1PR1-positive cells and that these cells accumulate toward the lumen because they follow the sphingosine-1-phosphate gradient from arterial wall tissue (low) to plasma (high).METHODS: A humanized rat model was used in which denuded human internal mammary artery (IMA) was implanted into the position of the abdominal aorta of immunosuppressed Rowett nude rats. This injury model is characterized by medial as well as intimal hyperplasia, whereby intimal cells are of human origin. At 7, 14, and 28 days after implantation, grafts were harvested and processed for fluorescent immunostaining for S1PR1 and smooth muscle α-actin. Nuclei were stained with 4',6-diamidine-2'-phenylindole dihydrochloride. Using digitally reconstructed, complete cross sections of grafts, intimal and medial areas were measured, whereby the medial area had virtually been divided into an outer (toward adventitia) and inner (toward lumen) layer. The fraction of S1PR1-positive cells was determined in each layer by counting S1PR1-positive and S1PR1-negative cells.RESULTS: The fraction of S1PR1-postive cells in naive IMA is 58.9% ± 6.0% (mean ± standard deviation). At day 28 after implantation, 81.6% ± 4.4% of medial cells were scored S1PR1 positive (P < .01). At day 14, the ratio between S1PR1-positive and S1PR1-negative cells was significantly higher in the lumen-oriented inner layer (9.3 ± 2.1 vs 6.0 ± 1.0; P < .01). Cells appearing in the intima at day 7 and day 14 were almost all S1PR1 positive. At day 28, however, about one-third of intimal cells were scored S1PR1 negative.CONCLUSIONS: From these data, we conclude that denudation of IMA specifically induces the expansion of S1PR1-positive cells. Based on the nonrandom distribution of S1PR1-positive cells, we consider the possibility that much like lymphocytes, S1PR1-positive smooth muscle cells also use S1PR1 to recognize the sphingosine-1-phosphate gradient from tissue (low) to plasma (high) and so migrate out of the media toward the intima of the injured IMA.
KW - Animals
KW - Aorta, Abdominal/surgery
KW - Cell Movement
KW - Cell Proliferation
KW - Disease Models, Animal
KW - Graft Occlusion, Vascular/etiology
KW - Humans
KW - Lysophospholipids/metabolism
KW - Male
KW - Mammary Arteries/metabolism
KW - Muscle, Smooth, Vascular/metabolism
KW - Myocytes, Smooth Muscle/metabolism
KW - Neointima
KW - Rats, Nude
KW - Receptors, Lysosphingolipid/metabolism
KW - Signal Transduction
KW - Sphingosine/analogs & derivatives
KW - Sphingosine-1-Phosphate Receptors
KW - Time Factors
U2 - 10.1016/j.jvs.2018.02.053
DO - 10.1016/j.jvs.2018.02.053
M3 - SCORING: Journal article
C2 - 29804740
VL - 68
SP - 201S-207S
JO - J VASC SURG
JF - J VASC SURG
SN - 0741-5214
IS - 6S
ER -