IGF-I prevents HIF-1α-dependent G1/S arrest by activating cyclin E/CDK2 via the PI3K/AKT/FOXO1/Cdkn1b pathway in porcine granulosa cells.

As the follicle develops， the thickening of the granulosa compartment leads to progressively deficient supply of oxygen in GCs due to the growing distances from the follicular vessels. These conditions are believed to cause hypoxia in GCs during folliculogenesis. Upon hypoxic conditions， several types of mammalian cells have been reported to undergo cell cycle arrest. However， it remains unclear whether hypoxia exerts any impact on cell cycle progression of GCs. On the other hand， although the GCs may live in a hypoxic environment， their mitotic capability appears to be unaffected in growing follicles. It thus raises the question whether there are certain intra-ovarian factors that might overcome the inhibitory effects of hypoxia. The present study provides the first evidence suggesting that CoCl2-mimicked hypoxia prevented G1-to-S cell cycle progression in porcine GCs. In addition， we demonstrated that the inhibitory effects of CoCl2 on GCs cell cycle are mediated through HIF-1α/FOXO1/Cdkn1b pathway. Moreover， we identified IGF-I as an intra-follicular factor required for cell cycle recovery by binding to IGFR in GCs suffering CoCl2 stimulation. Further investigations confirmed a role of IGF-I in preserving G1/S progression of CoCl2-treated GCs via activating the cyclin E/CDK2 complex through the PI3K/AKT/FOXO1/Cdkn1b axis. Although the present findings were based on a hypoxia mimicking model by using CoCl2， our study might shed new light on the regulatory mechanism of GCs cell cycle upon hypoxic stimulation.