Skip to main content
SpringerLink
Log in

Matrix Metalloproteinase 1 Causes Vasoconstriction and Enhances Vessel Reactivity to Angiotensin II via Protease-Activated Receptor 1

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

Abstract

Matrix metalloproteinase 1 (MMP-1) is an activator of protease-activated receptor 1 (PAR-1), which is known to mediate the release of endothelin 1 (ET-1) in endothelial cells and activate the RhoA kinase (ROCK) pathway. Recently, we reported increased serum and vascular MMP-1 in women with preeclampsia and hypothesized that the action of MMP-1 on PAR-1 might have vasoconstrictive effects. Resistance-sized omental arteries obtained from normal pregnant women were mounted on a myograph system and perfused with MMP-1 in a dose range of 0.025 to 25 ng/mL or with angiotensin II (Ang II) in a dose range of 0.001 to 10 µmol/L in the presence of intraluminal MMP-1 (2.5 ng/mL) perfusion. Angiotensin II dose response was also performed with omental arteries from women with preeclampsia. Matrix metalloproteinase 1 caused dose-dependent vasoconstriction in endothelium-intact, but not in endothelium-denuded, vessels from normal pregnant women, which was blocked by inhibitors of PAR-1 and ET-1 type A receptor blocker. Intraluminal perfusion with a constant amount of MMP-1 enhanced vessel reactivity to Ang II, which was blocked by inhibitors of PAR-1, ROCK, and ET-1. Enhanced vascular reactivity to Ang II was observed in endothelium-intact, but not in endothelium-denuded, arteries of women with preeclampsia. Inhibitors of PAR-1, ROCK, and ET-1 blocked enhanced vascular reactivity to Ang II in endothelium-intact preeclamptic arteries. These data demonstrate that MMP-1 has potent vasoconstrictor effects and the ability to enhance vascular reactivity to vasoconstrictor hormones, which are mediated by an endothelial PAR-1, ROCK, and ET-1 pathway. Increased circulating levels of MMP-1 and its increased expression in systemic vessels of women with preeclampsia may contribute to the development of maternal hypertension.

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. Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia:a systematic review. Eur J Obstet Gynecol Reprod Biol. 2013; 170(1):1–7.

    PubMed  Google Scholar 

  2. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010; 376(9741):631–644.

    PubMed  Google Scholar 

  3. Huppertz B, Weiss G, Moser G. Trophoblast invasion and oxygenation of the placenta:measurements versus presumptions. J Reprod Immunol. 2014; 101–102:74–79.

    Google Scholar 

  4. Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med. 1999; 222(3):222–235.

    CAS  PubMed  Google Scholar 

  5. Walsh SW. Matemal-placental interactions of oxidative stress and antioxidants in preeclampsia. Semin Reprod Endocrinol. 1998; 16(1):93–104.

    CAS  PubMed  Google Scholar 

  6. Walsh SW, Vaughan JE, Wang Y, Roberts LJ II. Placental iso-prostane is significantly increased in preeclampsia. FASEB J. 2000; 14(10):1289–1296.

    CAS  PubMed  Google Scholar 

  7. Clark P, Boswell F, Greer IA. The neutrophil and preeclampsia. Semin Reprod Endocrinol. 1998; 16(1):57–64.

    CAS  PubMed  Google Scholar 

  8. Gervasi MT, Chaiworapongsa T, Pacora P, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gynecol. 2001; 185(4):792–797.

    CAS  PubMed  Google Scholar 

  9. Greer IA, Haddad NG, Dawes J, Johnstone FD, Calder AA. Neutrophil activation in pregnancy-induced hypertension. Br J Obstet Gynaecol. 1989; 96(8):978–882.

    CAS  PubMed  Google Scholar 

  10. Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol. 1998; 179(1):80–86.

    CAS  PubMed  Google Scholar 

  11. Leik CE, Walsh SW. Neutrophils infiltrate resistance-sized vessels of subcutaneous fat in women with preeclampsia. Hypertension. 2004; 44(1):72–77.

    CAS  PubMed  Google Scholar 

  12. Cadden KA, Walsh SW. Neutrophils, but not lymphocytes or monocytes, infiltrate maternal systemic vasculature in women with preeclampsia. Hypertens Pregnancy. 2008; 27(4):396–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia:an endothelial cell disorder. Am J Obstet Gynecol. 1989; 161(5):1200–1204.

    CAS  PubMed  Google Scholar 

  14. Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin Reprod Endocrinol. 1998; 16(1):17–31.

    CAS  PubMed  Google Scholar 

  15. Shah TJ, Walsh SW. Activation of NF-kappaB and expression of COX-2 in association with neutrophil infiltration in systemic vascular tissue of women with preeclampsia. Am J Obstet Gynecol. 2007; 196(1):e1–e8.

    Google Scholar 

  16. Pei D. Matrix metalloproteinases target protease-activated receptors on the tumor cell surface. Cancer Cell. 2005; 7(3):207–208.

    CAS  PubMed  Google Scholar 

  17. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PARI is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005; 120(3):303–313.

    CAS  PubMed  Google Scholar 

  18. Ahn HS, Chackalamannil S, Boykow G, Graziano MP, Foster C. Development of proteinase-activated receptor I antagonists as therapeutic agents for thrombosis, restenosis and inflammatory diseases. Curr Pharm Des. 2003; 9(28):2349–2365.

    CAS  PubMed  Google Scholar 

  19. Trivedi V, Boire A, Tchemychev B, et al. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PARI at a cryptic ligand site. Cell. 2009; 137(2):332–343.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hanemaaijer R, Koolwijk P, le Clercq L, de Vree WJ, van Hinsbergh VW. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin I and phorbol ester. Biochem J. 1993; 296(3):e803–e809.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Grab DJ, Nyarko E, Barat NC, Nikolskaia OV, Dumler JS. Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cells. Clin Vaccine Immunol. 2007; 14(11):1420–1424.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhu Y, Hojo Y, Ikeda U, Takahashi M, Shimada K. Interaction between monocytes and vascular smooth muscle cells enhances matrix metalloproteinase-1 production. J Cardiovasc Pharmacol. 2000; 36(2):152–161.

    CAS  PubMed  Google Scholar 

  23. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006; 69(3):562–573.

    CAS  PubMed  Google Scholar 

  24. Nagase H, Suzuki K, Enghild JJ, Salvesen G. Stepwise activation mechanisms of the precursors of matrix metalloproteinases I (tissue collagenase) and 3 (stromelysin). Biomed Biochim Acta. 1991; 50(4–6):749–754.

    CAS  PubMed  Google Scholar 

  25. Estrada-Gutierrez G, Cappello RE, Mishra N, et al. Increased expression of matrix metalloproteinase-1 in systemic vessels of preeclamptic women:a critical mediator of vascular dysflmction. Am J Pathol. 2011; 178(1):451–460.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Coughlin SR. Protease-activated receptors in vascular biology. Thromb Haemost. 2001; 86(1):298–307.

    CAS  PubMed  Google Scholar 

  27. Eto M, Barandier C, Rathgeb L, et al. Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways:role of Rho/ROCK and mitogen-activated protein kinase. Circ Res. 2001; 89(7):583–590.

    CAS  PubMed  Google Scholar 

  28. Schini VB, Vanhoutte PM. Endothelin-1:a potent vasoactive peptide. Pharmacol Toxicol. 1991; 69(5):303–309.

    CAS  PubMed  Google Scholar 

  29. Buhl AM, Johnson NL, Dhanasekaran N, Johnson GL. G alpha 12 and G alpha 13 stimulate Rho-dependent stress fiber formation and focal adhesion assembly. J Biol Chem. 1995; 270(42):24631–24634.

    CAS  PubMed  Google Scholar 

  30. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005; 3(8):1800–1814.

    CAS  PubMed  Google Scholar 

  31. Mishra N, Nugent WH, Mahavadi S, Walsh SW. Mechanisms of enhanced vascular reactivity in preeclampsia. Hypertension. 2011; 58(5):867–873.

    CAS  PubMed  Google Scholar 

  32. Cao X, Luo T, Luo X, Tang Z. Resveratrol prevents AngII-induced hypertension via AMPK activation and RhoA/ROCK suppression in mice. Hypertens Res. 2014; 37(9):803–810.

    CAS  PubMed  Google Scholar 

  33. Abramovich DR, Page KR, Wright F. Effect of angiotensin II and 5-hydroxytryptamine on the vessels of the human foetal cotyledon. Br J Pharmacol. 1983; 79(1):53–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Maigaard S, Foiman A, Andersson KE. Differential effects of angiotensin, vasopressin and oxytocin on various smooth muscle tissues within the human uteroplacental unit. Acta Physiol Scand. 1986; 128(1):23–31.

    CAS  PubMed  Google Scholar 

  35. Mak KK, Gude NM, Walters WA, Boura AL. Effects of vasoactive autacoids on the human umbilical-fetal placental vasculature. Br JObstet Gynaecol. 1984; 91(2):99–106.

    CAS  Google Scholar 

  36. Tulenko TN. The actions of prostaglandins and cyclo-oxygenase inhibition on the resistance vessels supplying the human fetal placenta. Prostaglandins. 1981; 21(6):1033–1043.

    CAS  PubMed  Google Scholar 

  37. Aalkjaer C, Danielsen H, Johannesen P, Pedersen EB, Rasmussen A, Mulvany MJ. Abnormal vascular function and morphology in pre-eclampsia:a study of isolated resistance vessels. Clin Sci (Lond). 1985; 69(4):477–482.

    CAS  Google Scholar 

  38. Narumiya H, ZhangY, Fernandez-Patron C, Guilbert LJ, Davidge ST. Matrix metalloproteinase-2 is elevated in the plasma of women with preeclampsia. Hypertens Pregnancy. 2001; 20(2):185–194.

    CAS  PubMed  Google Scholar 

  39. Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999; 85(10):906–811.

    CAS  PubMed  Google Scholar 

  40. Abdalvand A, Morton JS, Bourque SL, Quon AL, Davidge ST. Matrix metalloproteinase enhances big-endothelin-1 constriction in mesenteric vessels of pregnant rats with reduced uterine blood flow. Hypertension. 2013; 61(2):488–493.

    CAS  PubMed  Google Scholar 

  41. Goerge T, Barg A, Schnaeker EM, et al. Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor I promoting endothelial cell activation. Cancer Res. 2006; 66(15):7766–7774.

    CAS  PubMed  Google Scholar 

  42. Urata H, Boehm KD, Philip A, et al. Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J Clin Invest. 1993; 91(4):1269–1281.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. van Mourik JA, Romani de Wit T, Voorberg J. Biogenesis and exocytosis of Weibel-Palade bodies. Histochem Cell Biol. 2002; 117(2):113–122.

    PubMed  Google Scholar 

  44. Marsen TA, Simonson MS, Dunn MJ. Thrombin induces the preproendothelin-1 gene in endothelial cells by a protein tyrosine kinase-linked mechanism. Circ Res. 1995; 76(6):987–895.

    CAS  PubMed  Google Scholar 

  45. Greer lA, Leask R, Hodson BA, Dawes J, Kilpatrick DC, Liston WA. Endothelin, elastase, and endothelial dysfunction in preeclampsia. Lancet. 1991; 337(8740):558.

    CAS  PubMed  Google Scholar 

  46. Taylor RN, Varma M, Teng NN, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab. 1990; 71(6):1675–1677.

    CAS  PubMed  Google Scholar 

  47. Mousa AA, Cappello RE, Estrada-Gutierrez G, et al. Preeclampsia is associated with alterations in DNA methylation of genes involved in collagen metabolism. Am J Pathol. 2012; 181(4):1455–1463.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shukla J, Walsh SW. Neutrophil release of myeloperoxidase in systemic vasculature of obese women may put them at risk for preeclampsia. Reprod Sci. 2015; 22(3):300–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest. 1973; 52(11):2682–2689.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Poole RM, Elkinson S. Vorapaxar:first global approval. Drugs. 2014; 74(10):1153–1163.

    CAS  PubMed  Google Scholar 

  51. Lohn M, Plettenburg O, Kannt A, et al. End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899. World J Cardiol. 2015; 7(1):31–42.

    PubMed  PubMed Central  Google Scholar 

  52. Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013; 77(10):2619–2625.

    CAS  PubMed  Google Scholar 

  53. Lee YH, Song GG. Meta-analysis of randomized controlled trials of bosentan for treatment of pulmonary arterial hypertension. Korean J Intern Med. 2013; 28(6):701–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hu J, Van den Steen PE, Sang QX, Opdenakker G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov. 2007; 6(6):480–498.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Virginia Commonwealth University Medical Center, P.O. Box 980034, 23298-0034, Richmond, VA, USA

    William H. Nugent PhD, Nikita Mishra MD, PhD, Jerome F. Strauss III MD, PhD & Scott W. Walsh PhD

  2. Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA

    Nikita Mishra MD, PhD & Scott W. Walsh PhD

Authors
  1. William H. Nugent PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikita Mishra MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerome F. Strauss III MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott W. Walsh PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott W. Walsh PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nugent, W.H., Mishra, N., Strauss, J.F. et al. Matrix Metalloproteinase 1 Causes Vasoconstriction and Enhances Vessel Reactivity to Angiotensin II via Protease-Activated Receptor 1. Reprod. Sci. 23, 542–548 (2016). https://doi.org/10.1177/1933719115607998

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115607998

Keywords

Search

Navigation