Smooth muscle relaxant molecules are implicated in the regulation of vascular adaptations during pregnancy and in normal uteroplacental function and fetal growth. The long-term goal of our research is to define the role of potent, smooth muscle relaxant, calcitonin gene-related peptide (CGRP) in these vascular adaptations and uteroplacental function. In the previous funding period, we found that both the expression of CGRP and the vasodilatory action of CGRP are upregulated during pregnancy and by sex-steroid hormones. However, the mechanisms of CGRP-induced vasodilation as well as the involvement of CGRP in uterine and placental blood flow regulation are not known. Thus, the overall goal of this application is to determine the mechanisms of CGRP-induced vasorelaxation of mesenteric artery and assess the involvement of CGRP in uteroplacental blood flow in the rat. Hypotheses to be tested are: 1) that the increased CGRP-induced mesenteric artery relaxation during pregnancy is due to elevated expression of CGRP receptor components, caicitonin receptor-like receptor (CRLR) and receptor signaling modifying protein (RAMP1), and their post-receptor signaling, and 2) CGRP is involved in the regulation of uteroplacental blood flow and fetal growth.
Three specific aims are proposed.
Specific aim 1 : to characterize CGRP receptors and post-receptor signaling in the mesenteric artery and describe the regulation of the receptors during rat pregnancy and by the sex-steroid hormones. We will measure changes in CRLR and RAMP1, post-receptor signaling and arterial relaxation of mesenteric artery, and assess CGRP-induced blood flow throughout gestation and assess their regulation by sex-steroid hormones.
Specific aim 2 : to examine the vasodilatory effects of CGRP on uterine artery and assess if these effects are regulated by pregnancy and sex-steroid hormones. We will measure changes in CRLR, RAMP1 and post-receptor signaling and relaxation of uterine artery, and assess CGRP-induced blood flow throughout gestation and regulation by steroid hormones.
Specific aim 3 : to investigate the role of CGRP in placental blood flow. We will measure changes in CRLR, RAMP1 and CGRP binding in placenta throughout late gestation and their influence by sex-steroid hormones and assess CGRP-induced blood flow through placenta. These studies would help assess the involvement of CGRP in vascular adaptations and in fetal growth during pregnancy and lay a foundation for assessing therapeutic value of CGRP in pregnancy.
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