Skip to main content
SpringerLink
Log in

Contractility and Calcium Signaling of Human Myometrium Are Profoundly Affected by Cholesterol Manipulation: Implications for Labor?

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The authors elucidate cholesterol’s effect on human uterine contractility and calcium signaling to test the hypotheses that elevation of cholesterol decreases uterine activity and that oxytocin cannot augment contraction when cholesterol is elevated. The effects of cholesterol extraction with methyl β -cyclodextrin and enrichment with low-density lipoproteins and cholesterol on contractile activity and intracellular calcium signaling in spontaneous or oxytocin-stimulated myometrium are determined. Force occurring spontaneously and with oxytocin is significantly increased by cholesterol extraction. Cholesterol enrichment profoundly inhibits force production in a dose-dependent manner and could reverse the effects of cholesterol extraction. Qualitatively similar results are found for nonpregnant and pregnant laboring and non-laboring myometrium. These contractile changes are related to changes in intracellular Ca2 +. Thus, elevated cholesterol is deleterious to contractility and Ca2 + signaling in human myometrium. Cholesterol may contribute to uterine quiescence but could cause difficulties in labor in obese/dyslipidemic women, consistent with their increased cesarean delivery rates

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Thomas J, Callwood A, Paranjothy S. National Sentinel Caesarean Section Audit: update. Pract Midwife. 2000;3(11):20.

    CAS  PubMed  Google Scholar 

  2. Crane SS, Wojtowycz MA, Dye TD, Aubry RH, Artal R. Association between pre-pregnancy obesity and the risk of cesarean delivery. Obstet Gynecol. 1997;89(2):213–216.

    Article  CAS  PubMed  Google Scholar 

  3. Weiss JL, Malone FD, Emig D, et al. Obesity, obstetric complications and cesarean delivery rate—a population-based screening study. Am J Obstet Gynecol. 2004;190(4): 1091–1097.

    Article  PubMed  Google Scholar 

  4. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol. 2004;103(2):219–224.

    Article  PubMed  Google Scholar 

  5. Tilton Z, Hodgson MI, Donoso E, Arteaga A, Rosso P. Complications and outcome of pregnancy in obese women. Nutrition. 1989;5(2):95–99.

    CAS  PubMed  Google Scholar 

  6. Zhang J, Bricker L, Wray S, Quenby S. Poor uterine contractility in obese women. BJOG. 2007;114(3):343–348.

    Article  CAS  PubMed  Google Scholar 

  7. Vahratian A, Zhang J, Troendle JF, Savitz DA, Siega-Riz AM. Maternal prepregnancy overweight and obesity and the pattern of labor progression in term nulliparous women. Obstet Gynecol. 2004;104(5 pt 1):943–951.

    Article  PubMed  Google Scholar 

  8. Samsonov AV, Mihalyov I, Cohen FS. Characterization of cholesterol-sphingomyelin domains and their dynamics in bilayer membranes. Biophys J. 2001;81(3):1486–1500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fujita T, Toya Y, Iwatsubo K, et al. Accumulation of molecules involved in a1-adrenergic signal within caveolae: caveolin expression and the development of cardiac hypertrophy. Cardiovasc Res. 2001;51(4):709–716.

    Article  CAS  PubMed  Google Scholar 

  10. Ishizaka N, Griendling KK, Lassegue B, Alexander RW. Angiotensin II type 1 receptor: relationship with caveolae and caveolin after initial agonist stimulation. Hypertension. 1998; 32(3):459–466.

    Article  CAS  PubMed  Google Scholar 

  11. Nakayama K, Obara K, Tanabe Y, Saito M, Ishikawa T, Nishizawa S. Interactive role of tyrosine kinase, protein kinase C, and Rho/Rho kinase systems in the mechanotransduction of vascular smooth muscles. Biorheology. 2003;40(1):307–314.

    CAS  PubMed  Google Scholar 

  12. Babiychuk EB, Monastyrskaya K, Burkhard FC, Wray S, Draeger A. Modulating signaling events in smooth muscle: cleavage of annexin 2 abolishes its binding to lipid rafts. FASEB J. 2002;16(10):1177–1184.

    Article  CAS  PubMed  Google Scholar 

  13. Taggart MJ, Leavis P, Feron O, Morgan KG. Inhibition of PKCalpha and rhoA translocation in differentiated smooth muscle by a caveolin scaffolding domain peptide. Exp Cell Res. 2000;258(1):72–81.

    Article  CAS  PubMed  Google Scholar 

  14. Smith RD, Babiychuk EB, Noble K, Draeger A, Wray S. Increased cholesterol decreases uterine activity: functional effects of cholesterol in pregnant rat myometrium. Am J Physiol. 2005;288(5):C982–C988.

    Article  CAS  Google Scholar 

  15. Turi A, Kiss AL, Mullner N. Estrogen downregulates the number of caveolae and the level of caveolin in uterine smooth muscle. Cell Biol Int. 2001;25(8):785–794.

    Article  CAS  PubMed  Google Scholar 

  16. Babiychuk EB, Smith RD, Burdyga TV, Babiychuk VS, Wray S, Draeger A. Membrane cholesterol selectively regulates smooth muscle phasic contraction. J Membr Biol. 2004; 198(2):95–101.

    Article  CAS  PubMed  Google Scholar 

  17. Dreja K, Voldstedlund M, Vinten J, Tranum-Jensen J, Hellstrand P, Sward K. Cholesterol depletion disrupts caveolae and differentially impairs agonist-induced arterial contraction. Arterioscler Thromb Vasc Biol. 2002;22(8):1267–1272.

    Article  CAS  PubMed  Google Scholar 

  18. Noble K, Zhang J, Wray S. Lipid rafts, the sarcoplasmic reticulum and uterine calcium signalling: an integrated approach. J Physiol. 2006;570(pt 1):29–35.

    Article  CAS  PubMed  Google Scholar 

  19. Gimpl G, Fahrenholz F. Human oxytocin receptors in cholesterol-rich vs. cholesterol-poor microdomains of the plasma membrane. Eur J Biochem. 2000;267(9):2483–2497.

    Article  CAS  PubMed  Google Scholar 

  20. Kim BK, Ozaki H, Hori M, Takahashi K, Karaki H. Increased contractility of rat uterine smooth muscle at the end of pregnancy. Comp Biochem Physiol A Mol Integr Physiol. 1998; 121(2):165–173.

    CAS  Google Scholar 

  21. Gostynski M, Gutzwiller F, Kuulasmaa K, et al. Analysis of the relationship between total cholesterol, age, body mass index among males and females in the WHO MONICA Project. Int J Obes Relat Metab Disord. 2004;28(8):1082–1090.

    Article  CAS  PubMed  Google Scholar 

  22. Podedinsky NM. Serum lipid composition in obese pregnant patients. Akusherstvo I Ginekologiia Moskva. 1987;6:22–26.

    Google Scholar 

  23. Pulkkinen MO, Nyman S, Hamalainen MM, Mattinen J. Proton NMR spectroscopy of the phospholipids in human uterine smooth muscle and placenta. Gynecol Obstet Invest. 1998;46(4):220–224.

    Article  CAS  PubMed  Google Scholar 

  24. Luckas Mjm, Wray S. A comparison of the contractile properties of human myometrium obtained from the upper and lower uterine segments. Br J Obstet Gynaecol. 2000;107(10):1309–1311.

    Article  CAS  Google Scholar 

  25. Taggart MJ, Menice CB, Morgan KG, Wray S. Effect of metabolic inhibition on intracellular Ca2+, phosphorylation of myosin regulatory light chain and force in rat smooth muscle. J Physiol Lond. 1997;499:485–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kupittayanant S, Burdyga ThV, Wray S. The effects of inhibiting Rho-associated kinase on force and intracellular calcium in human myometrium. Pflugers Arch. 2001;443(1): 112–114.

    Article  CAS  PubMed  Google Scholar 

  27. Luckas Mjm, Taggart MJ, Wray S. Intracellular calcium stores and agonist induced contractions in human myometrium. Am J Obstet Gynecol. 1999;181(2):468–476.

    Article  CAS  PubMed  Google Scholar 

  28. Jennings LJ, Xu QW, Firth TA, Nelson MT, Mawe GM. Cholesterol inhibits spontaneous action potentials and calcium currents in guinea pig gallbladder smooth muscle. Am J Physiol. 1999;277(5 pt 1):G1017–G1026.

    CAS  PubMed  Google Scholar 

  29. Smith RD, Barrow SL, Babiychuck EB, Wray S. Depletion of membrane cholesterol: effects on rat myometrial spontaneous force and calcium. J Physiol. 2003;552:C9.

    Google Scholar 

  30. Bergdahl A, Gomez MF, Dreja K, et al. Cholesterol depletion impairs vascular reactivity to endothelin-1 reducing store-operated Ca2+ entry dependent on TRPC-1. Circ Res. 2003;93:839–847.

    Article  CAS  PubMed  Google Scholar 

  31. Wray S, Jones K, Kupittayanant S, et al. Calcium signaling and uterine contractility. J Soc Gynecol Investig. 2003;10(5):252–264.

    Article  CAS  PubMed  Google Scholar 

  32. Wray S, Kupittayanant S, Shmigol A, Smith RD, Burdyga TV. The physiological basis of uterine contractility: a short review. Exp Physiol. 2001;86(2):239–246.

    Article  CAS  PubMed  Google Scholar 

  33. Shmygol A, Noble K, Wray S. Depletion of membrane cholesterol eliminates the Ca2+-activated component of outward potassium current and decreases membrane capacitance in rat uterine myocytes. J Physiol. 2007;581(pt 2):445–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sampson LJ, Hayabuchi Y, Standen NB, Dart C. Caveolae localize protein kinase A signaling to arterial ATP-sensitive potassium channels. Circ Res. 2004;95(10):1012–1018.

    Article  CAS  PubMed  Google Scholar 

  35. Brainard AM, Miller AJ, Martens JR, England SK. Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current. Am J Physiol Cell Physiol. 2005;289(1):C49–C57.

    Article  CAS  PubMed  Google Scholar 

  36. Raber J, Bast A. Changes in receptor response by the effect of disease on membrane fluidity. Med Hypotheses. 1989;28(3):169–171.

    Article  CAS  PubMed  Google Scholar 

  37. Squier TC, Bigelow DJ, Thomas DD. Lipid fluidity directly modulates the overall protein rotational mobility of the Ca-ATPase in sarcoplasmic reticulum. J Biol Chem. 1988; 263(19): 9178–9186.

    CAS  PubMed  Google Scholar 

  38. Fong TM, McNamee MG. Stabilization of acetylcholine receptor secondary structure by cholesterol and negatively charged phospholipids in membranes. Biochem. 1987;26(13):3871–3880.

    Article  CAS  Google Scholar 

  39. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1(1):31–39.

    Article  CAS  PubMed  Google Scholar 

  40. Ramsay JE, Ferrell W, Crawford L, Wallace M, Greer IE, Sattar NJ. Maternal obesity is associated with dysregulation of metabolic vascular and inflammatory pathways. J Clin Endocrinol Metab. 2002;87(9):4231–4237.

    Article  CAS  PubMed  Google Scholar 

  41. Massey JB, Pownall HJ. Surface properties of native human plasma lipoproteins and lipoprotein models. Biophys J. 1998;74(2 pt 1):869–878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Deighan CJ, Caslake MJ, McConnell M, Boulton-Jones JM, Packard CJ. Patients with nephrotic-range proteinuria have apolipoprotein C and E deficient VLDL1. Kidney Int. 2000; 58(3):1238–1246.

    Article  CAS  PubMed  Google Scholar 

  43. Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ. Inhibitory effect of leptin on human uterine contractility in vitro 16. Am J Obstet Gynecol. 2006;195(2):504–509.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK

    Jie Zhang MBBS, Siobhan Quenby MD & Susan Wray PhD

  2. Liverpool Women’s Hospital, Liverpool, UK

    Annabelle Kendrick MBBS

Authors
  1. Jie Zhang MBBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annabelle Kendrick MBBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Siobhan Quenby MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan Wray PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan Wray PhD.

Additional information

The authors acknowledge Wellbeing of Women for financial support; Drs E. Babiychuk, T. Burdyga, and A. Draeger for useful discussion; and the staff and patients at Liverpool Women’s Hospital. Jie Zhang is supported by an Overseas Research Student award.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, J., Kendrick, A., Quenby, S. et al. Contractility and Calcium Signaling of Human Myometrium Are Profoundly Affected by Cholesterol Manipulation: Implications for Labor?. Reprod. Sci. 14, 456–466 (2007). https://doi.org/10.1177/1933719107306229

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719107306229

Key words

Search

Navigation