Sex hormones induce death or cell proliferation in various cell lines and in primary cultures. However, the signal transduction pathways involved in the regulation of proliferation and apoptosis in endothelial cells have not been fully elucidated. Here, we report that progesterone and testosterone induce apoptosis in HUVECs in a p38- and JNK-dependent manner, and that estradiol promotes proliferation via the activation of ERK2. We showed that, at physiological doses, progesterone and testosterone promoted p38, but not JNK, phosphorylation. Hormone inhibitors, on the other hand, prevented p38 phosphorylation. When supraphysiological doses were applied, both p38 and JNK were phosphorylated, causing apoptotic cell death. The addition of hormone inhibitors at an appropriate concentration did not prevent cell death or the phosphorylation of p38 and JNK. Estradiol, at physiological doses, promoted an increase in ERK2 phosphorylation that was blocked by fulvestrant. At physiological and supraphysiological doses, it promoted a proliferative effect. In conclusion, these findings suggest that JNK has an important pro-apoptotic function following progesterone and testosterone treatment in human endothelial cells, and that ERK2 has a proliferative effect following estradiol treatment.

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