The Role of the RHOA/ROCK Pathway in the Regulation of Myometrial Stages Throughout Pregnancy

Overview

Journal AJOG Glob Rep

Specialty Gynecology & Obstetrics

Date 2024 Oct 22

PMID 39434813

Authors

Jorge A Carvajal

Jose Galaz

Sofia Villagran

Rocio Astudillo

Liliana Garmendia

Ana Maria Delpiano

Affiliations

Soon will be listed here.

Abstract

Background: Controlling uterine contractile activity is essential to regulate the duration of pregnancy. During most of the pregnancy, the uterus does not contract (i.e., myometrial quiescence). The myometrium recovers its contractile phenotype at around 36 weeks (i.e., myometrial activation) through several mechanisms. The RHOA/ROCK pathway plays a vital role in facilitating muscular contractions by calcium sensitization in humans. Yet, the role of this pathway during different myometrial stages, including quiescence, has not been elucidated.

Objective: we aimed to study the role of the RHOA/ROCK pathway in the regulation of the different myometrial stages throughout pregnancy. Specifically, we hypothesized that the inhibition of the components of the RHOA/ROCK pathway play an important role in maintaining uterine quiescence.

Study Design: Myometrial samples were obtained from pregnant individuals who underwent cesarean section. Pregnant individuals who delivered preterm without labor (myometrial quiescence), preterm with labor (nonphysiological myometrial stimulation), term not in labor (activation), and term in labor (physiological myometrial stimulation) were included. The mRNA and protein expression of RHOA, ROCK I, ROCK II, RND1-3, and ROCK activity through pMYTP1 were evaluated.

Results: We found that the human myometrium constitutively expressed RHOA/ROCK pathway components throughout pregnancy. No changes in the components of the RHOA/ROCK pathway were found during quiescence. Moreover, the RHOA protein and ROCK activity increased in the myometrium during labor, supporting the hypothesis that this pathway participates in maintaining the contractile activity of the myometrium. This study provides insight into the role of the RHOA/ROCK pathway in controlling myometrial contractile activity during pregnancy.

References

Van Aelst L, DSouza-Schorey C . Rho GTPases and signaling networks. Genes Dev. 1997; 11(18):2295-322. DOI: 10.1101/gad.11.18.2295. View

Bros M, Haas K, Moll L, Grabbe S . RhoA as a Key Regulator of Innate and Adaptive Immunity. Cells. 2019; 8(7). PMC: 6678964. DOI: 10.3390/cells8070733. View

Mason C, Swaan P, Weiner C . Identification of interactive gene networks: a novel approach in gene array profiling of myometrial events during guinea pig pregnancy. Am J Obstet Gynecol. 2006; 194(6):1513-23. DOI: 10.1016/j.ajog.2005.12.044. View

Weiner C, Mason C, Dong Y, Buhimschi I, Swaan P, Buhimschi C . Human effector/initiator gene sets that regulate myometrial contractility during term and preterm labor. Am J Obstet Gynecol. 2010; 202(5):474.e1-20. PMC: 2867841. DOI: 10.1016/j.ajog.2010.02.034. View

Sharkey J, Cable C, Olcese J . Melatonin sensitizes human myometrial cells to oxytocin in a protein kinase C alpha/extracellular-signal regulated kinase-dependent manner. J Clin Endocrinol Metab. 2010; 95(6):2902-8. PMC: 2902072. DOI: 10.1210/jc.2009-2137. View

Mendelson C, Gao L, Montalbano A . Multifactorial Regulation of Myometrial Contractility During Pregnancy and Parturition. Front Endocrinol (Lausanne). 2019; 10:714. PMC: 6823183. DOI: 10.3389/fendo.2019.00714. View

Aguan K, Carvajal J, Thompson L, Weiner C . Application of a functional genomics approach to identify differentially expressed genes in human myometrium during pregnancy and labour. Mol Hum Reprod. 2000; 6(12):1141-5. DOI: 10.1093/molehr/6.12.1141. View

Lopez Bernal A, Rivera J, Europe-Finner G, Phaneuf S, Asboth G . Parturition: activation of stimulatory pathways or loss of uterine quiescence?. Adv Exp Med Biol. 1995; 395:435-51. View

Gomez-Lopez N, StLouis D, Lehr M, Sanchez-Rodriguez E, Arenas-Hernandez M . Immune cells in term and preterm labor. Cell Mol Immunol. 2014; 11(6):571-81. PMC: 4220837. DOI: 10.1038/cmi.2014.46. View

10.

Motomura K, Romero R, Galaz J, Miller D, Done B, Arenas-Hernandez M . Human Chorionic Gonadotropin Modulates the Transcriptome of the Myometrium and Cervix in Late Gestation. Reprod Sci. 2021; 28(8):2246-2260. PMC: 8500204. DOI: 10.1007/s43032-020-00454-6. View

11.

Villalonga P, Ridley A . Rho GTPases and cell cycle control. Growth Factors. 2006; 24(3):159-64. DOI: 10.1080/08977190600560651. View

12.

Lartey J, Smith M, Pawade J, Strachan B, Mellor H, Lopez Bernal A . Up-regulation of myometrial RHO effector proteins (PKN1 and DIAPH1) and CPI-17 (PPP1R14A) phosphorylation in human pregnancy is associated with increased GTP-RHOA in spontaneous preterm labor. Biol Reprod. 2007; 76(6):971-82. DOI: 10.1095/biolreprod.106.058982. View

13.

Smith R . Parturition. N Engl J Med. 2007; 356(3):271-83. DOI: 10.1056/NEJMra061360. View

14.

Romero R, Espinoza J, Goncalves L, Kusanovic J, Friel L, Nien J . Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006; 11(5):317-26. PMC: 8315239. DOI: 10.1016/j.siny.2006.05.001. View

15.

Peterson L, Stelzer I, Tsai A, Ghaemi M, Han X, Ando K . Multiomic immune clockworks of pregnancy. Semin Immunopathol. 2020; 42(4):397-412. PMC: 7508753. DOI: 10.1007/s00281-019-00772-1. View

16.

Foster R, Hu K, Lu Y, Nolan K, Thissen J, Settleman J . Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation. Mol Cell Biol. 1996; 16(6):2689-99. PMC: 231259. DOI: 10.1128/MCB.16.6.2689. View

17.

Bishop A, Hall A . Rho GTPases and their effector proteins. Biochem J. 2000; 348 Pt 2:241-55. PMC: 1221060. View

18.

Riento K, Guasch R, Garg R, Jin B, Ridley A . RhoE binds to ROCK I and inhibits downstream signaling. Mol Cell Biol. 2003; 23(12):4219-29. PMC: 156133. DOI: 10.1128/MCB.23.12.4219-4229.2003. View

19.

Menon R, Bonney E, Condon J, Mesiano S, Taylor R . Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum Reprod Update. 2016; 22(5):535-60. PMC: 5001499. DOI: 10.1093/humupd/dmw022. View

20.

Lartey J, Gampel A, Pawade J, Mellor H, Lopez Bernal A . Expression of RND proteins in human myometrium. Biol Reprod. 2006; 75(3):452-61. DOI: 10.1095/biolreprod.105.049130. View