Evidence for Decreased Calcitonin Gene-Related Peptide (CGRP) Receptors and Compromised Responsiveness to CGRP of Fetoplacental Vessels in Preeclamptic Pregnancies

Abstract

Calcitonin gene-related peptide (CGRP) is a potent vasodilatory peptide, and its concentration is increased in both maternal and fetal circulation during late pregnancy. The present study was designed to investigate the expression of CGRP receptor components, calcitonin receptor-like receptor (CRLR), and receptor activity modifying protein 1 (RAMP1), and the relaxation response to CGRP in fetoplacental vessels from normotensive pregnant women and women with preeclampsia. Results showed that: 1) mRNA for both CRLR and RAMP1 was expressed in fetoplacental vessels from normal pregnancies; however, these mRNA expressions were substantially reduced in the vessels from preeclamptic women; 2) CRLR and RAMP1 proteins were abundantly expressed in the endothelium and smooth muscle layer of the fetoplacental vessels, as well as the trophoblast cells in normal placentas. In contrast, both vascular tissues and trophoblasts showed decreased expressions for CRLR and RAMP1 proteins and declined CGRP binding sites in preeclamptic placentas; and 3) CGRP produced a dose-dependent relaxation of serotonin-induced contraction of umbilical and chorionic arteries from normal pregnancies, but the response to CGRP was significantly attenuated in the vessels from preeclampsia. We concluded that CGRP may contribute to the low fetoplacental vascular resistance in normal pregnancies; however, CGRP-dependent vascular relaxation appears to be compromised in preeclamptic pregnancies.

Molecular Regulation of Human Placental Growth Factor (PlGF) Gene Expression in Placental Villi and Trophoblast Cells is Mediated via the Protein Kinase A Pathway

“…1 Preeclampsia is characterized by hypertension and proteinuria and is associated with low levels of CGRP and CRLR mRNA in placental samples. [38][39][40][41] However, some reports indicate that AM mRNA and protein may be increased in the placentae and fetoplacental circulation of women with PE and IUGR. [42][43][44] A more thorough comprehension of how PlGF is regulated during normal pregnancy is an important prerequisite to understanding its abnormal secretion, as observed in the serum of women developing pregnancy-related diseases like PE and IUGR.…”

Pregnant Rats Treated With a Serotonin Precursor Have Reduced Fetal Weight and Lower Plasma Volume and Kallikrein Levels

“…Serotonin has a marked vasoconstrictor effect on umbilical and chorionic arteries, suggesting that it may play a role in the regulation of placental blood flow. 32,33 In addition, serotonin receptors have been found in several reproductive organs, including normal human placental tissue. 34,35 Rats treated with 5-HTP had elevated serotonin levels in amniotic fluid, indicating that either 5-HTP is metabolized at this level and/or that serotonin crosses the placental barrier.…”

Role of Nitric Oxide in Mediating In Vivo Vascular Responses to Calcitonin Gene-Related Peptide in Essential and Peripheral Circulations in the Fetus

“…10 The increased maternal plasma levels of CGRP during pregnancy, 11 its presence in human cord and neonatal blood, and the finding that the concentration of CGRP in fetal serum correlates with both fetal weight and gestational age 12 indicate a functional role for CGRP in prenatal life. This is further supported by evidence from Dong and colleagues, 13,14 who have demonstrated the presence of components of the CGRP receptor in the vascular endothelium and smooth muscle cells of human fetoplacental vessels, and by Terenghi and colleagues, 15 who have detected CGRP within the human nervous system during the first trimester of pregnancy. However, little is known about the actions of CGRP in the fetal vasculature.…”

“…24 The biological actions of CGRP are mediated predominantly through the CGRP 1 receptor, which is made up of the calcitonin receptor-like receptors and RAMP1 proteins, both of which have been demonstrated within the endothelium and underlying smooth muscle cells of human fetoplacental vessels. 13,14 Unlike classic vasodilators, CGRP elicited cardiovascular responses, which were particularly long-lasting. CGRP has a half-life of Ϸ7 to 10 minutes in the adult circulation, 25 and its vasodilator activity is removed after clearance by several mechanisms, including those involving mast cell tryptase, 26 neutral endopeptidases, 27 matrix metalloproteinase-2, 28 or reuptake mechanisms into the sensory nerve terminal after repolarization.…”