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Differential regulation of smooth muscle cell phenotype by sphingosine‐1‐phosphate receptors.
Author(s) -
Wamhoff Brian R,
Lynch Kevin,
Owens Gary K
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a699-c
Subject(s) - sphingosine 1 phosphate , receptor , microbiology and biotechnology , biology , sphingosine 1 phosphate receptor , vascular smooth muscle , myosin , inflammation , cell growth , phenotype , signal transduction , actin , sphingosine , immunology , endocrinology , gene , genetics , smooth muscle
A hallmark of smooth muscle cell (SMC) phenotypic modulation in vascular injury and inflammation is suppression of SMC differentiation marker genes and induction of genes required for proliferation and migration leading to vessel narrowing. Sphingosine‐1‐phosphate (S1P) is a bioactive lipid in the blood, released by platelets during inflammation and has diverse vascular functions. SMCs express the S1P1, S1P2 and S1P3 receptors. Treatment of SMCs with S1P induced SMC proliferation and increased c‐fos. Paradoxically, S1P also increased expression of the SMC differentiation marker genes SM α‐actin and SM myosin heavy chain (SMMHC). We tested the hypothesis that SMC phenotypic modulation is differentially regulated by specific S1P receptors. Blocking S1P1 and S1P3 receptors with selective antagonists potentiated S1P‐induced activation of SM α‐actin/SMMHC and prevented the increase in c‐fos and SMC proliferation. Conversely, inhibition of the S1P2 receptor prevented S1P‐induced expression of SM α‐actin/SMMHC and potentiated S1P‐induced SMC proliferation. S1P1 and S1P3 receptor mRNA levels were transiently increased 36‐fold and 5‐fold 24 hrs following rat carotid injury whereas S1P2 expression was decreased by 90%, consistent with SMC proliferation. Conversely, 10 days post injury, S1P2 receptor expression was transiently increased 12‐fold, consistent with re‐induction of the differentiated SMC phenotype. These results provide evidence that S1P2 receptors promote SMC differentiation and S1P1 and S1P3 receptors mediate SMC proliferation, revealing a new role for S1P signaling in adult SMCs and phenotypic switching in response to vascular injury.