Intermedin is an Estrogen- Modulated Factor for Reducing Blood Pressure

Calcitonin, calcitonin gene-related peptides (CGRPs), adrenomedullin, and amylin belong to a unique group of peptide hormones important for the regulation of calcium balance, neurotransmission, cardiovascular homeostasis, and glucose metabolism. We, the investigators at Chang Gung Memorial Hospital, recently identified intermedin as a novel peptide hormone belonging to this unique peptide ligand family. Adrenomedullin is a 52-amino-acid peptide and is one of the most potent vasodilators. Plasma adrenomedullin is elevated in a variety of pathological conditions such as hypertension, renal failure, heart failure, and septic shock. CGRPα and CGRPβ are 37-amino acid neuropeptides; primarily release from sensory nerves; and play important roles in regulating peripheral vascular tone and controlling blood flow in various organs. Human mature intermedin encodes 40-amino-acid and is expressed mainly in the adrenocorticotrophs of the anterior and intermediate pituitary lobe. Intermedin signals through calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein (RAMP) receptor complexes, and CRLR/RAMP signaling has been proven to be critical for vascular tone regulation. Based on this finding, we had documented that intraperitoneal administration of intermedin dose-dependently suppressed blood pressure in normal Sprague-Dawley rats. In addition, our preliminary in vitro and in vivo studies demonstrated that ovariectomy lead to a tenfold reduction of intermedin transcript expression in the pituitary in rats whereas subsequent estrogen treatment increased pituitary intermedin expression to a level similar to that of intact rats. Taken together, we propose that pituitary-derived intermedin is regulated by estrogen and exhibits potent hypotensive effects. To address this hypothesis, in Specific Aim 1, we will investigate the regulation of secretion and expression of intermedin in vitro and in vivo using cultured pituitary cells and oophorectomized rats. In Specific Aim 2, we will study the molecular mechanism by which estrogen stimulates intermedin gene expression. In Specific Aim 3, to demonstrate that the estrogen-dependent regulation of intermedin represents a critical link in the regulation of blood pressure in women, we will study the relationship between blood pressure and blood intermedin levels using a cross-sectional study. Our studies will provide a better understanding of the mechanisms by which sex hormones modulate blood pressure and open a new window for postmenopausal hypertension treatment.