27-hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen

The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27- hydroxycholesterol ( 27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription- mediated and the non- transcription- mediated estrogen- dependent production of nitric oxide by vascular cells, resulting in reduced estrogen- induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet- induced hypercholesterolemia, pharmacologic administration or genetic manipulation ( by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen- dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell- type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator ( SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.