Premium
Sphingosine Kinase‐1 regulates VEGF‐A induced angiogenesis by mediating the interaction between VEGFR2 and S1P1
Author(s) -
Chavez Alejandra M.,
Chava Koteshwara Rao,
Mehta Dolly
Publication year - 2012
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.26.1_supplement.841.2
Subject(s) - angiogenesis , microbiology and biotechnology , sphingosine kinase 1 , sphingosine kinase , sphingosine 1 phosphate , vascular endothelial growth factor a , sphingosine , kinase insert domain receptor , matrigel , s1pr1 , biology , endothelial stem cell , vascular endothelial growth factor , chemistry , receptor , cancer research , vegf receptors , in vitro , biochemistry
Sphingosine‐1‐phosphate (S1P) and vascular endothelial growth factor A (VEGFA) are critical in angiogenesis, which is characterized by cell responses like migration and proliferation. Sphingosine kinase‐1 (SPHK1) generates S1P from sphingosine and activates sphingosine‐1‐phosphate receptor 1 (S1P1) to maintain endothelial barrier function. Herein, we address the hypothesis that SPHK1 activation of S1P1 is required for mediating angiogenesis by VEGFA. We show that SPHK1 depleted human endothelial cells (ECs) or SPHK −/− ECs fail to migrate and from tube networks. In vivo we also find less blood vessel arborization and lumen formation in Matrigel plugs from SPHK −/− mice. Surprisingly, adding VEGFA to SPHK1 depleted ECs did not rescue the defects. Knock down (KD) of S1P1 prevented VEGFA induced angiogenesis while S1P restored tube formation and migration in SPHK1 KD cells, thus indicating that SPHK1→S1P→S1P1 axis is required for VEGFA induced angiogenesis. Since VEGF receptor 2 (VEGFR2) primarily regulates VEGFA induced angiogenesis we focused on it. We found that SPHK1 KD altered the activation of VEGFR2 downstream effectors and suppressed cell surface VEGFR2 localization. We further show that VEGFR2 pulls down S1P1 in naïve ECs but fails to interact in SPHK1 depleted ECs. Our data identify a novel role of SPHK1 in mediating interaction between VEGFR2 and S1P1 that is required for VEGFA to induce angiogenesis.