G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention

Conrad, Kirk P.

doi:10.1093/humupd/dmw021

Cited by 36 publications

(25 citation statements)

References 228 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, unveiling aberrant endometrial gene expression on endometrial biopsy of women in late secretory phase who were affected by severe preeclampsia in a prior pregnancy could inform targeted investigation and discovery of protein biomarkers in blood, urine or uterine feven before conception that eventually could constitute a diagnostic panel. Ultimately, designing interventions that improve endometrial maturation to facilitate normal placentation and reduce preeclampsia risk might be a logical therapeutic course of action [118]. …”

Section: Perspectivesmentioning

confidence: 99%

Emerging role for dysregulated decidualization in the genesis of preeclampsia

2017

Self Cite

View full text Add to dashboard Cite

In normal human placentation, uterine invasion by trophoblast cells and subsequent spiral artery remodeling depend on cooperation among fetal trophoblasts and maternal decidual, myometrial, immune and vascular cells in the uterine wall. Therefore, aberrant function of anyone or several of these cell-types could theoretically impair placentation leading to the development of preeclampsia. Because trophoblast invasion and spiral artery remodeling occur during the first half of pregnancy, the molecular pathology of fetal placental and maternal decidual tissues following delivery may not be informative about the genesis of impaired placentation, which transpired months earlier. Therefore, in this review, we focus on the emerging prospective evidence supporting the concept that deficient or defective endometrial maturation in the late secretory phase and during early pregnancy, i.e., pre-decidualization and decidualization, respectively, may contribute to the genesis of preeclampsia. The first prospectively-acquired data directly supporting this concept were unexpectedly revealed in transcriptomic analyses of chorionic villous samples (CVS) obtained during the first trimester of women who developed preeclampsia 5 months later. Additional supportive evidence arose from investigations of Natural Killer cells in first trimester decidua from elective terminations of women with high resistance uterine artery indices, a surrogate for deficient trophoblast invasion. Last, circulating insulin growth factor binding protein-1, which is secreted by decidual stromal cells was decreased during early pregnancy in women who developed preeclampsia. We conclude this review by making recommendations for further prospectively-designed studies to corroborate the concept of endometrial antecedents of preeclampsia. These studies could also enable identification of women at increased risk for developing preeclampsia, unveil the molecular mechanisms of deficient or defective (pre)decidualization, and lead to preventative strategies designed to improve (pre)decidualization, thereby reducing risk for preeclampsia development.

show abstract

Section: Perspectivesmentioning

confidence: 99%

Emerging role for dysregulated decidualization in the genesis of preeclampsia

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pregnancy hormone relaxin is now recognized as a potential vascular treatment for preeclampsia . Relaxin is produced by the corpus luteum, placenta, and uterus .…”

Section: No Pathwaymentioning

confidence: 99%

“…Additionally, relaxin and the relaxin mimetic B7‐33 protect the mesenteric artery of female mice from endothelial dysfunction induced by trophoblast‐conditioned media high in sFlt‐1 . Importantly, relaxin administration ex vivo significantly reduces myogenic constriction of human subcutaneous arteries from preeclamptic women …”

Section: No Pathwaymentioning

confidence: 99%

“…It remains to be established if these beneficial effects of relaxin are associated with enhanced vasoconstriction or reduced agonist‐dependent relaxation. In an sFlt‐1 adenovirus animal model of preeclampsia, sFlt‐1 increases myogenic constriction in small renal arteries, while relaxin treatment inhibits this increase in myogenic constriction . The next phase of relaxin research will further assess relaxin's vascular actions in vivo, in preparation for a pilot trial in pregnant women.…”

Section: No Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Targeting the vascular dysfunction: Potential treatments for preeclampsia

et al. 2019

View full text Add to dashboard Cite

Preeclampsia is a pregnancy-specific disorder clinically characterized by new-onset hypertension (>20 weeks' gestation) with one or more of proteinuria and maternal organ dysfunction such as renal insufficiency, liver dysfunction, neurological complications, fetal growth restriction, or uteroplacental dysfunction. 1,2 Each year, preeclampsia is the principal cause of death in over 60 000 women and in more than 500 000 babies globally. 3 The pathophysiological mechanisms underlying the disease are still not entirely clear. Briefly, In 2017, Sarah was awarded her PhD at the University of Melbourne, Australia, and is currently an NHMRC Peter Doherty Research Fellow in the Department of Obstetrics and Gynecology at Monash University, Australia. The focus of her research is to assess the potential of new and old therapeutics to target the vascular dysfunction of preeclampsia, and translate these studies into clinical application. AbstractPreeclampsia is a pregnancy-specific disorder, primarily characterized by new-onset hypertension in combination with a variety of other maternal or fetal signs. The pathophysiological mechanisms underlying the disease are still not entirely clear.Systemic maternal vascular dysfunction underlies the clinical features of preeclampsia. It is a result of oxidative stress and the actions of excessive anti-angiogenic factors, such as soluble fms-like tyrosine kinase, soluble endoglin, and activin A, released by a dysfunctional placenta. The vascular dysfunction then leads to impaired regulation and secretion of relaxation factors and an increase in sensitivity/production of constrictors. This results in a more constricted vasculature rather than the relaxed vasodilated state associated with normal pregnancy. Currently, the only effective "treatment" for preeclampsia is delivery of the placenta and therefore the baby.Often, this means a preterm delivery to save the life of the mother, with all the attendant risks and burdens associated with fetal prematurity. To lessen this burden, there is a pressing need for more effective treatments that target the maternal vascular dysfunction that underlies the hypertension. This review details the vascular effects of key drugs undergoing clinical assessment as potential treatments for women with preeclampsia.

show abstract

“…Due to their ability to control a wide array of biological functions, GPCR-based signaling activity has become perhaps the primary target for effective therapeutic research. GPCR-based regulation of cellular pathological mechanisms has shown tremendous clinical relevance for neurodegenerative (Maudsley et al, 2007; Huang et al, 2017), metabolic (Martin et al, 2017; Riddy et al, 2018), neoplastic (Liu et al, 2016), respiratory (Douthwaite et al, 2017), and cardiovascular (Conrad, 2016) disorders. As studies continue to uncover further nuances in GPCR regulatory behavior, new roles, aside from simple receptor phosphorylation, for GRKs in GPCR systems have emerged.…”

Section: Introductionmentioning

confidence: 99%

GRK5 – A Functional Bridge Between Cardiovascular and Neurodegenerative Disorders

et al. 2018

View full text Add to dashboard Cite

Complex aging-triggered disorders are multifactorial programs that comprise a myriad of alterations in interconnected protein networks over a broad range of tissues. It is evident that rather than being randomly organized events, pathophysiologies that possess a strong aging component such as cardiovascular diseases (hypertensions, atherosclerosis, and vascular stiffening) and neurodegenerative conditions (dementia, Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease), in essence represent a subtly modified version of the intricate molecular programs already in place for normal aging. To control such multidimensional activities there are layers of trophic protein control across these networks mediated by so-called “keystone” proteins. We propose that these “keystones” coordinate and interconnect multiple signaling pathways to control whole somatic activities such as aging-related disease etiology. Given its ability to control multiple receptor sensitivities and its broad protein-protein interactomic nature, we propose that G protein coupled receptor kinase 5 (GRK5) represents one of these key network controllers. Considerable data has emerged, suggesting that GRK5 acts as a bridging factor, allowing signaling regulation in pathophysiological settings to control the connectivity between both the cardiovascular and neurophysiological complications of aging.

show abstract

G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention

Cited by 36 publications

References 228 publications

Emerging role for dysregulated decidualization in the genesis of preeclampsia

Emerging role for dysregulated decidualization in the genesis of preeclampsia

Targeting the vascular dysfunction: Potential treatments for preeclampsia

GRK5 – A Functional Bridge Between Cardiovascular and Neurodegenerative Disorders

Contact Info

Product

Resources

About