Progesterone-mediated angiogenic activity of endothelial progenitor cell and angiogenesis in traumatic brain injury rats were antagonized by progesterone receptor antagonist.

OBJECTIVES: Progesterone (P4) has the potential therapeutic effects for traumatic brain injury (TBI) whose recovery depended on the enhanced angiogenesis. Endothelial progenitor cell (EPC) plays an essential role in vascular biology. We previously demonstrated that P4 administration improved circulating EPC level and neurological recovery of rat with TBI. Here, we hypothesized that P4 augmented angiogenic potential of EPC and the angiogenesis-related neurorestoration after TBI through classical progesterone receptor (PR).

MATERIALS AND METHODS: EPC derived from rats were stimulated with graded concentrations (0, 10(-10) , 10(-9) , 5 × 10(-9) , 10(-8) , 10(-7)  mol/L) of P4 or 10(-6)  mol/L ulipristal acetate (UPA, a PR antagonist). Male rats were subjected to cortical impact injury and treated with (i) DMSO (dimethyl sulfoxide), (ii) P4 and (iii) P4 and UPA.

RESULTS: It showed that P4 improved the angiogenic potential of EPC, including tube formation, adhesion, migration and vascular endothelial growth factor secretion, in a dose-dependent fashion with the maximal effect achieved at 10(-9)  mol/L P4. High concentration (10(-7)  mol/L) of P4 impaired the angiogenic potential of EPC. Notably, 10(-6)  mol/L UPA antagonized the stimulatory effects of 10(-9 ) mol/L P4. After administrating P4, a significant improvement of neurological function and the restoration of the leaked blood-brain barrier were observed as well as a reduction of the brain water content. Both vessel density and expression of occludin of vessels were increased. When UPA was administered with P4, the neural restoration and angiogenesis were all reversed. Western blot showed that 10(-9)  mol/L P4 increased the content of PRA and PRB of EPC, while 10(-7)  mol/L P4 reduced the content of both PR isoforms, but there was no change found in the TBI rats.

CONCLUSIONS: It may suggest that P4-mediated angiogenic activity of EPC and angiogenesis in TBI rats were antagonized by PR antagonist.