| Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme of the catecholamine biosynthetic pathway and is responsible for the synthesis of epinephrine. Epinephrine is produced mainly in adrenal glands and in small quantities in the brainstem. Epinephrine is involved in blood pressure regulation and increased levels have been associated with the pathogenesis of hypertension. Brainstem adrenergic neurons regulate blood pressure and are able to stimulate the major site for epinephrine synthesis via the hypothalamic-pituitary-adrenal and the sympatho-adrenal axes, therefore linking them to the pathogenesis of hypertension. Genetic mapping and microarray studies linked overexpression of PNMT to hypertension in humans and in genetic models of hypertension. It has also been shown that stress during fetal development can program hypertension later in life. Furthermore, studies have found that these effects are passed down to future generations, a phenomenon known as transgenerational programming. Altered transcriptional regulation of the PNMT gene in the brainstem was hypothesized as an important factor responsible for the overproduction of epinephrine and ultimately the pathogenesis of hypertension. Results presented propose that elevated levels of regulator Egr-1 may genetically account for overproduction of PNMT in all three adrenergic regions of hypertensive rats. In addition, fetal stress induces dysregulation of the PNMT gene, via increased Egr-1, GR, and AP-2, leading to enhanced PNMT promoter activity in the adrenergic neuron regions of the brainstem. Furthermore, these increases intensified in subsequent generations after prenatally stressed rats. These findings propose that altered PNMT gene regulation may contribute to enhanced epinephrine synthesis that instigates hypertension in all three animal models. |
