Pre-Eclampsia-Associated Reduction in Placental Growth Factor Impaired Beta Cell Proliferation Through PI3k Signalling.
OBJECTIVE
Reduction in serum placental growth factor (PLGF) frequently co-occurs with preeclampsia (PE) and gestational diabetes mellitus (GDM). Recently, we reported that impairment in gestational beta-cell mass growth may result from PE-associated reduction in PLGF and lead to development of GDM. Here, we studied the underlying mechanisms.


METHODS
We co-cultured primary mouse beta cells with mouse islet endothelial cells (MS1), with or without PLGF. We also cultured beta cells in conditioned media from PLGF-treated MS1. Specific signal-pathway inhibitors were applied to cultured beta cells in conditioned media from PLGF-treated MS1. We analysed beta-cell proliferation by BrdU incorporation. We analysed changes in cell number by a MTT assay. We analysed protein levels of cell-cycle regulators in beta cells by Western blot.


RESULTS
PLGF itself failed to induce beta-cell proliferation, but significantly augmented proliferation of beta cells co-cultured with MS1, which resulted in significant increases in cell number. Conditioned media from the PLGF-treated MS1 cells similarly induced beta-cell proliferation, which was abolished by inhibition of PI3k/Akt signalling, but not by inhibition of either ERK/MAPK or JNK signalling. The induction of beta-cell proliferation by PLGF-treated MS1 cells appeared to involve decreases in cell-cycle inhibitors p21 and p27, and increases in cell-cycle activators CDK4 and CyclinD1.


CONCLUSIONS
Gestational PLGF may target islet endothelial cells to release growth factors that activate PI3k/Akt signalling in beta cells to increase their proliferation. PE-associated reduction in PLGF impairs these processes to result in GDM.
Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical University, Shenyang, China.
Jun
J
Li
Huanchun
H
Ying
Guiyang
G
Cai
Quan
Q
Guo
Lizhu
L
Chen
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D016640:Diabetes, Gestational / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D019869:Phosphatidylinositol 3-Kinases