The maintenance of adequate blood flow to the placenta is essential for a successful pregnancy. Increased fetoplacental vascular resistance and reduced blood flow seen in intrauterine growth restriction (IUGR) and/or preeclampsia is associated with increased fetal and neonatal morbidity and mortality. Calcitonin gene-related peptide (CGRP) has been demonstrated to be involved in the regulation of blood pressure and myometrial contractility during pregnancy via its potent smooth muscle relaxant property, but its role as a vasodilator in physiological and pathological fetoplacental circulation is poorly understood. We have new evidence that CGRP receptors are present in the rat placenta and progressively increase as gestation advances. In addition, CGRP peptide is present in fetal plasma at a higher concentration than that in maternal circulation in late pregnancies. CGRP mRNA is abundantly expressed in the fetal dorsal root ganglia (DRG) and progressively enhanced at term. In humans, CGRP relaxes umbilical, chorionic, and stem villous arteries in a dose-dependent fashion indicating that endogenous CGRP may help maintain low fetoplacental vascular tone during pregnancy. To assess the role of CGRP in the control of human fetoplacental vascular tone, we have proposed the following Specific Aims:
Specific Aim 1 : To characterize CGRP receptors in the human fetoplacental vasculature. We will identify the cellular location and distribution of CGRP receptor component CRLR and RAMP1 in fetoplacental vessels, and assess radio ligand CGRP binding affinities and capacities.
Specific Aim 2 : To assess the vasodilatory effects of CGRP on fetoplacental vessels, and determine if they are altered with advancing gestation and modulated by steroid hormones.
Specific Aim 3 : To determine the post-receptor signaling pathway of CGRP-induced fetoplacental vascular relaxation.
Specific Aim 4 : To determine the role of CGRP in altered fetoplacental vascular reactivity in IUGR and/or preeclampsia, and evaluate whether insufficient CGRP-related vasodilator mechanisms were involved in the pathophysiology of IUGR and/or preeclampsia. Our long-term goal is to define the role of CGRP in the regulation of fetoplacental circulation and vascular adaptation during pregnancy. This proposal will have important basic science and clinical implications. Our results may indicate that CGRP has vasodilatory effects on human fetoplacental vasculature and is regulated by sex steroid hormones, as well as elucidate the role of CGRP in IUGR and/or preeclampsia.
