SEX STEROID HORMONES AND CALCITONIN GENE RELATED PEPTIDE

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Female sex steroids profoundly influence the vascular system. Several mechanisms have been proposed for the vascular effects. We have obtained new evidence which implicates sensory neuropeptide calcitonin gene- related peptide (CGRP) as an important modulator of the female sex steroid actions in cardiovascular reactivity in normal and pregnant females. Based upon our preliminary studies, we propose three interrelated hypotheses: 1) es-tradiol and progesterone regulate neuronal CGRP expression in female (nonpregnant and pregnant) rats which in turn influence vascular tone, 2) progesterone modulates the CGRP effector systems, the mechanism of which is through the upregulation of vascular CGRP receptors, and thus modulates vasodilator actions of CGRP, 3) the expression and effects of CGRP in females are enhanced during pregnancy and CGRP plays a compensatory vasodilator role to attenuate hypertension during pregnancy. Three specific aims are proposed to test these three hypotheses. Specific Aim 1: To determine whether alterations in CGRP expression in female rat dorsal root ganglia (DRG) are related to changes in sex steroid hormones and to investigate the mechanisms involved. We will determine the effects of steroid hormones estradiol and progesterone on the expression of CGRP, nerve growth factor (NGF) and NGF receptors using a) in vivo animal models and b) primary cultures of DRG neurons. Specific Aim 2: To determine whether sex steroid hormones modulate the hemodynamic effects of CGRP in females. We will assess the effects of sex steroid hormones on a) CGRP- induced hemodynamic changes and regional organ blood flow using radioactive microsphere technique, b) relaxation responsiveness of resistance vessels to CGRP, c) vascular CGRP receptors and postreceptor transduction pathway. Specific Aim 3: To determine whether neuronal CGRP expression and the hemodynamic effects of CGRP are altered during pregnancy and evaluate whether CGRP plays a compensatory vasodilator role to attenuate the elevated blood pressure during pregnancy-induced hypertension. Long-term goals: This proposal will have important basic scientific and clinical implications. The results may indicate whether sex steroid hormones regulate the expression of CGRP and the hemodynamic effects of CGRP in females and will also help to understand the role of CGRP in modulating vascular adaptations during pregnancy and in compensatory hemodynamics to attenuate hypertension during pregnancy. The results of these studies would lay the foundation for future studies of involvement of CGRP and sex steroid hormones in the pathophysiology of hypertension in females and preeclampsia.