Context: The insulin/IGF system regulates fetal and placental growth and development. In a pregnancy complicated by maternal diabetes, placentas are hypervascularized and fetal insulin levels are elevated. In the fetal circulation, insulin can act on the placenta through insulin receptors present on the fetoplacental endothelial cells.
Objective: We hypothesized that insulin exerts proangiogenic effects on the fetoplacental endothelial cells, thereby contributing to the placental hypervascularization in diabetes.
Design: The effect of insulin on angiogenesis and proliferation of human fetoplacental endothelial cells was investigated by a 2-dimensional network formation assay, staining for actin fibers, automatic cell counting, and cell cycle analysis. The signaling pathways involved were identified using antibodies against activated signaling proteins and pharmacological inhibitors.
Results: Insulin enhanced network formation by 23% (P < .05%) and caused actin reorganization. Insulin stimulated (P < .05) phosphorylation of insulin receptor (+320%), and insulin receptor substrate-1 (+140%), Akt (+177%), glycogen-synthase kinase-β3 (+70%), and endothelial nitric oxide synthase (eNOS; +100%) increased nitric oxide production and activated Ras-related C3 botulinum toxin substrate 1 (Rac1). Insulin did not induce ERK1/2 phosphorylation or proliferation. Inhibition of phosphatidylinositol 3-kinase, eNOS, and Rac1 signaling abolished the effects on network formation.
Conclusions: Elevated fetal insulin levels may contribute to the placental hypervascularization in diabetes via the phosphatidylinositol 3-kinase/Akt/eNOS pathway and involve Rac1. However, insulin does not stimulate proliferation and may need to cooperate with other growth factors.