Many cellular responses to steroid hormones involve the transcriptional modulation of target genes by the prototypical nuclear receptor, the steroid hormone receptor. In the classic model of steroid hormone action, steroid hormones such as estrogen and glucocorticoids function essentially as ligand dependent transcription factors by either activating or repressing gene expression through direct interactions with DNA or other transcription factors. However, recent evidence suggests an important role for the nontranscriptional effects of steroid hormones in the vascular system, particularly in endothelial cells (ECs), where they mediate the rapid activation of endothelial nitric oxide synthase (eNOS).

For example, the activated estrogen receptor (ER) mediates signaling cascades that culminate in direct protective effects such as vasodilation, inhibition of response to vessel injury, limiting myocardial injury after infarction, and attenuating cardiac hypertrophy. These effects of ER are mediated by rapid signaling pathways at the membrane and in the cytoplasm via various second messengers including protein kinases. Similarly, the nontranscriptional actions of the glucocorticoid receptor (GR) involve the rapid activation of protein kinases, such as phosphoinositide 3-kinase (PI3K) and Akt, leading to the activation of eNOS. These rapid, nongenomic pathways of estrogen and glucocorticoids may provide the pharmacological basis for future therapeutic approaches to cardiovascular diseases (Table 180–1).

SIGNALING PATHWAYS MEDIATED BY STEROID HORMONES

The study of steroid hormone action has provided many important insights into the regulation of cellular functions by nuclear receptors and, at the same time, has revealed surprising levels of biological complexity.