Vasoprotective role of female sex steroid hormones: Involvement of CGRP

The incidence of such cardiovascular diseases as coronary heart disease and hypertension can be decreased in postmenopausal women by use of female hormone replacement therapy. Moreover, the female sex steroid hormones, estradiol and progesterone, may play a role in the vascular adaptations that occur during pregnancy. The mechanisms involved in the vasoprotection exerted by these hormones are not fully understood. To examine these mechanisms, calcitonin gene-related peptide (CGRP), a potent vasodilator, has been used to treat congestive heart failure and to reduce preeclampsia-like symptoms in L-nitro arginine methyl ester (L-NAME)-treated pregnant rats. The primary site of CGRP synthesis is the cell bodies of sensory neurons in dorsal root ganglia (DRG) that send processes centrally to the spinal cord and peripherally to various tissues, including blood vessels. It has been shown that the presence of nerve growth factor (NGF) is required for female steroid hormone-induced CGRP synthesis in cultured DRG. Furthermore, NGF receptors are increased in DRG of the proestrus rats. Previous studies also show that both plasma CGRP levels and the ability of CGRP to lower blood pressure are increased when these female hormones are elevated. In this dissertation, these experiments examined whether CGRP synthesis in DRG is elevated via upregulation of NGF receptors following the increased female sex steroid hormone levels seen in pregnancy and after hormone injections in nonpregnant rats. The studies also investigated whether pregnancy and female sex steroid hormone administration increase both CGRP release at the perivascular nerves and the sensitivity of a resistance vessel, the mesenteric artery, to CGRP-induced relaxation via elevations of CGRP receptor (CGRP-R). In this dissertation, the findings showed that pregnancy and ovarian steroid hormones increase CGRP synthesis and NGF receptors in DRG. Both pregnancy and these steroid hormones also partially modulate CGRP stored in the nerves around the mesenteric artery and vascular sensitivity to CGRP via CGRP-R and/or postreceptor mechanisms. Therefore, I suggest that CGRP may be at least one of the neuropeptides that plays a role in both the vascular adaptations that occur during pregnancy and in the vasoprotection associated with hormone replacement therapy in postmenopausal women.