Follicular fluid high density lipoprotein-associated sphingosine 1-phosphate is a novel mediator of ovarian angiogenesis.
Angiogenesis plays an important role in the development of the ovarian follicle and its subsequent transition into the corpus luteum. Accordingly, follicular fluid is a rich source of mitogenic and angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor secreted by granulosa cells. In the present study, we show that follicular fluid deprived of basic fibroblast growth factor or vascular endothelial growth factor by means of thermal denaturation or antibody neutralization retains its capacity to stimulate endothelial proliferation and angiogenesis. Mass spectrometric analysis of chromatographic fractions stimulating endothelial growth obtained from follicular fluid revealed that the heat-stable mitogenic activity is identical with the subfraction alpha of high density lipoproteins purified from follicular fluid (FF-HDL). Further investigations demonstrated that sphingosine 1-phosphate (S1P), one of the lysophospholipids associated with HDL, accounts for the capacity of this lipoprotein to stimulate endothelial growth and the formation of new vessels. Activation of mitogen-activated protein kinase (p42/44(ERK1/2)), protein kinase C, and protein kinase Akt represent signaling pathways utilized by FF-HDL and S1P to induce endothelial proliferation and angiogenesis. We conclude that FF-HDL represents a novel mitogenic and angiogenic factor present in follicular fluid and that S1P is one of the FF-HDL lipid components accounting for this activity.
von Otte
Sören
S
Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. svonotte@gmx.de
Paletta
Jürgen R J
JR
Becker
Steffi
S
König
Simone
S
Fobker
Manfred
M
Greb
Robert R
RR
Kiesel
Ludwig
L
Assmann
Gerd
G
Diedrich
Klaus
K
Nofer
Jerzy-Roch
JR
D000906:Antibodies / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015571:Follicular Fluid / Q000737:chemistry*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010053:Ovary / Q000098:blood supply / Q000502:physiology; D011489:Protein Denaturation; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000906:Antibodies; D008076:Cholesterol, HDL; D008246:Lysophospholipids; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C060506:sphingosine 1-phosphate; D013110:Sphingosine