Download PDF
Thromb Haemost 2008; 99(03): 586-593
DOI: 10.1160/TH07-11-0694
Endothelium and Vascular Development
Schattauer GmbH

Magnesium maintains endothelial integrity, up-regulates proteolysis of ultra-large von Willebrand factor, and reduces platelet aggregation under flow conditions

Jing-fei Dong
1   Section of Thrombosis Research
2   Section of Hematology/Oncology, Department of Medicine
,
Miguel A. Cruz
1   Section of Thrombosis Research
,
Khatira Aboulfatova
1   Section of Thrombosis Research
,
Cecilia Martin
1   Section of Thrombosis Research
,
Hiuwan Choi
1   Section of Thrombosis Research
,
Angela L. Bergeron
1   Section of Thrombosis Research
,
Sheryl R. Martini
3   Department of Neurology, Baylor College of Medicine and the Michael E. DeBakey VA Medical Center Stroke Program, Houston, Texas, USA
,
Michael H. Kroll
1   Section of Thrombosis Research
2   Section of Hematology/Oncology, Department of Medicine
,
Thomas A. Kent
3   Department of Neurology, Baylor College of Medicine and the Michael E. DeBakey VA Medical Center Stroke Program, Houston, Texas, USA
› Author Affiliations Financial support: This work was supported by NIH grants HL71895, HL72886, and HD39833. J.F.D is an Established Investigator of the American Heart Association.
Further Information

Publication History

Received: 20 November 2007

Accepted after major revision: 23 January 2008

Publication Date:
07 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Mg ++ regulates endothelial functions and has anti-inflammatory effects. Its effects on thrombosis have been demonstrated, but the mechanism remains poorly understood.We investigated the roles of MgSO4 in regulating the release and cleavage of the prothrombotic ultra-large (UL) von Willebrand factor (VWF) and VWF-mediated platelet adhesion and aggregation.Washed platelets were perfused over cultured endothelial cells from human umbilical cord veins under a shear stress of 2.5 dyn/cm2. Release and cleavage of ULVWF by ADAMTS-13 was measured in the absence or presence of physiological or therapeutic levels of MgSO4. Whole blood or plasma-free reconstituted blood was perfused over immobilized collagen to measure the effect of MgSO4 on platelet adhesion and aggregation. Also studied were the effects of MgSO4 on ristocetin-induced platelet aggregation andVWF-collagen interaction.Maintenance of endothelial integrity required physiological levels of MgSO4, but exogenous MgSO4 showed no additional benefits.Exogenous MgSO4 significantly enhanced the cleavage of the newly released ULVWF strings by ADAMTS-13 and markedly reduced platelet aggregation on immobilized collagen under flow conditions.This effect is likely to be mediated through VWF as Mg++ partially inhibited ristocetin-induced platelet aggregation andVWF binding to collagen.MgSO4 is critical for maintaining endothelial integrity and regulates ULVWF proteolysis and aggregation under flow conditions. These results provide a new insight into additional mechanisms involved with magnesium therapy.

Keywords

Magnesium - endothelium - platelets - ADAMTS-13
 

  • References

  • 1 Mazur A, Maier JA, Rock E. et al. Magnesium and the inflammatory response: potential physiopathological implications. Arch Biochem Biophys 2007; 458: 48-56.
    CrossrefPubMedGoogle Scholar
  • 2 Bo S, Pisu E. Role of dietary magnesium in cardiovascular disease prevention, insulin sensitivity and diabetes. Curr Opin Lipidol 2008; 19: 50-56.
    CrossrefPubMedGoogle Scholar
  • 3 Rukshin V, Azarbal B, Shah PK. et al. Intravenous magnesium in experimental stent thrombosis in swine. Arterioscler Thromb Vasc Biol 2001; 21: 1544-1549.
    CrossrefPubMedGoogle Scholar
  • 4 Rukshin V, Shah PK, Cercek B. et al. Comparative antithrombotic effects of magnesium sulfate and the platelet glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in a canine model of stent thrombosis. Circulation 2002; 105: 1970-1975.
    CrossrefPubMedGoogle Scholar
  • 5 Rukshin V, Santos R, Gheorghiu M. et al. A prospective, nonrandomized, open-labeled pilot study investigating the use of magnesium in patients undergoing nonacute percutaneous coronary intervention with stent implantation. J Cardiovasc Pharmacol Ther 2003; 8: 193-200.
    CrossrefPubMedGoogle Scholar
  • 6 Shechter M, Merz CN, Paul-Labrador M. et al. Beneficial antithrombotic effects of the association of pharmacological oral magnesium therapy with aspirin in coronary heart disease patients. Magnes Res 2000; 13: 275-284.
    PubMedGoogle Scholar
  • 7 Thogersen AM, Jansson JH, Wester PO. Magnesium therapy, fibrinolytic parameters and von Willebrand factor in acute myocardial infarction. Int J Cardiol 1996; 56: 53-59.
    CrossrefPubMedGoogle Scholar
  • 8 Zweifler RM, Voorhees ME, Mahmood MA. et al. Magnesium sulfate increases the rate of hypothermia via surface cooling and improves comfort. Stroke 2004; 35: 2331-2334.
    CrossrefPubMedGoogle Scholar
  • 9 Hwang DL, Yen CF, Nadler JL. Effect of extracellular magnesium on platelet activation and intracellular calcium mobilization. Am J Hypertens 1992; 5: 700-706.
    CrossrefPubMedGoogle Scholar
  • 10 Cowan DH, Robertson AL, Shook P. et al. Platelet adherence to collagen: role of plasma, ADP, and divalent cations. Br J Haematol 1981; 47: 257-267.
    CrossrefPubMedGoogle Scholar
  • 11 Shechter M, Merz CN, Rude RK. et al. Low intracellular magnesium levels promote platelet-dependent thrombosis in patients with coronary artery disease. Am Heart J 2000; 140: 212-218.
    CrossrefPubMedGoogle Scholar
  • 12 Booth JV, Phillips-Bute B, McCants CB. et al. Low serum magnesium level predicts major adverse cardiac events after coronary artery bypass graft surgery. Am Heart J 2003; 145: 1108-1113.
    CrossrefPubMedGoogle Scholar
  • 13 Muir KW. Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. CNS Drugs 2001; 15: 921-930.
    CrossrefPubMedGoogle Scholar
  • 14 Muir KW, Lees KR, Ford I. et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 2004; 363: 439-445.
    CrossrefPubMedGoogle Scholar
  • 15 Saver JL, Kidwell C, Eckstein M. et al. Intravenous magnesium for neuroprotection in acute stroke: Neuropharmacology supports clinical hope. (Response). Stroke 2004; 35: e106-e108.
    CrossrefPubMedGoogle Scholar
  • 16 Bongers TN, De Maat MP, Van Goor ML. et al. High von Willebrand factor levels increase the risk of first ischemic stroke: influence ofADAMTS13, inflammation, and genetic variability. Stroke 2006; 37: 2672-2677.
    CrossrefPubMedGoogle Scholar
  • 17 Uchiyama S, Takeuchi M, Osawa M. et al. Platelet function tests in thrombotic cerebrovascular disorders. Stroke 1983; 14: 511-517.
    CrossrefPubMedGoogle Scholar
  • 18 Kario K, Matsuo T, Kobayashi H. et al. Hyperinsulinemia and haemostatic abnormalities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects. J Am Coll Cardiol 2001; 37: 871-877.
    CrossrefPubMedGoogle Scholar
  • 19 Kozuka K, Kohriyama T, Nomura E. et al. Endothelial markers and adhesion molecules in acute ischemic stroke–sequential change and differences in stroke subtype. Atherosclerosis 2002; 161: 161-168.
    CrossrefPubMedGoogle Scholar
  • 20 Tohgi H, Utsugisawa K, Yoshimura M. et al. Local variation in expression of pro- and antithrombotic factors in vascular endothelium of human autopsy brain. Acta Neuropathol (Berl) 1999; 98: 111-118.
    CrossrefPubMedGoogle Scholar
  • 21 Yagita Y, Kitagawa K, Sasaki T. et al. Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia. J Neurosci Res 2007; 85: 2460-2469.
    CrossrefPubMedGoogle Scholar
  • 22 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424.
    CrossrefPubMedGoogle Scholar
  • 23 Arya M, Anvari B, Romo GM. et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib- IX complex: studies using optical tweezers. Blood 2002; 99: 3971-3977.
    CrossrefPubMedGoogle Scholar
  • 24 Dong JF, Moake JL, Nolasco L. et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100: 4033-4039.
    CrossrefPubMedGoogle Scholar
  • 25 Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost 2005; 3: 1710-1716.
    CrossrefPubMedGoogle Scholar
  • 26 Nguyen TC, Liu A, Liu L. et al. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Hemtologica 2007; 92: 121-124.
    PubMedGoogle Scholar
  • 27 Moake JL, Turner NA, Stathopoulos NA. et al. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78: 1456-1461.
    CrossrefPubMedGoogle Scholar
  • 28 Tao Z, Anthony K, Peng Y. et al. Novel ADAMTS-13 mutations in an adult with delayed onset thrombotic thrombocytopenic purpura. J Thromb Haemost 2006; 4: 1931-1935.
    CrossrefPubMedGoogle Scholar
  • 29 Bernardo A, Bergeron AL, Sun CW. et al. Von Willebrand factor present in fibrillar collagen enhances platelet adhesion to collagen and collagen-induced platelet aggregation. J Thromb Haemost 2004; 2: 660-669.
    CrossrefPubMedGoogle Scholar
  • 30 Morales LD, Martin C, Cruz MA. The interaction of von Willebrand factor-A1 domain with collagen: mutation G1324S (type 2M von Willebrand disease) impairs the conformational change in A1 domain induced by collagen. J Thromb Haemost 2006; 4: 417-425.
    CrossrefPubMedGoogle Scholar
  • 31 Dong JF, Whitelock J, Bernardo A. et al. Variations among normal individuals in the cleavage of endothelial- derived ultra-large von Willebrand factor under flow. J Thromb Haemost 2004; 2: 1460-1466.
    CrossrefPubMedGoogle Scholar
  • 32 Sheu JR, Hsiao G, Shen MY. et al. Mechanisms involved in the antiplatelet activity of magnesium in human platelets. Br J Haematol 2002; 119: 1033-1041.
    CrossrefPubMedGoogle Scholar
  • 33 Whiss PA, Andersson RG. Divalent cations and the protein surface co-ordinate the intensity of human platelet adhesion and P-selectin surface expression. Blood Coagul Fibrinolysis 2002; 13: 407-416.
    CrossrefPubMedGoogle Scholar
  • 34 del Zoppo GJ, Milner R. Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 2006; 26: 1966-1975.
    CrossrefPubMedGoogle Scholar
  • 35 Takagi J, Sudo Y, Saito T. et al. Beta 1-integrin-mediated adhesion of melanoma cells to the propolypeptide of von Willebrand factor. Eur J Biochem 1994; 222: 861-867.
    CrossrefPubMedGoogle Scholar
  • 36 Maier JA, Bernardini D, Rayssiguier Y. et al. High concentrations of magnesium modulate vascular endothelial cell behaviour in vitro. Biochim Biophys Acta 2004; 1689: 6-12.
    CrossrefPubMedGoogle Scholar
  • 37 Maier JA, Malpuech-Brugere C, Zimowska W. et al. Low magnesium promotes endothelial cell dysfunction: implications for atherosclerosis, inflammation and thrombosis. Biochim Biophys Acta 2004; 1689: 13-21.
    CrossrefPubMedGoogle Scholar
  • 38 Dickens BF, Weglicki WB, Li YS. et al. Magnesium deficiency in vitro enhances free radical-induced intracellular oxidation and cytotoxicity in endothelial cells. FEBS Lett 1992; 311: 187-191.
    CrossrefPubMedGoogle Scholar
  • 39 Kawano H, Yokoyama S, Smith TL. et al. Effect of magnesium on secretion of platelet-derived growth factor by cultured human umbilical arterial endothelial cells. Magnes Res 1995; 8: 137-144.
    PubMedGoogle Scholar
  • 40 Bernardini D, Nasulewic A, Mazur A. et al. Magnesium and microvascular endothelial cells: a role in inflammation and angiogenesis. Front Biosci 2005; 10: 1177-82.
    CrossrefPubMedGoogle Scholar
  • 41 Furlan M, Robles R, Lammle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996; 87: 4223-4234.
    PubMedGoogle Scholar
  • 42 Kokame K, Matsumoto M, Soejima K. et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 2002; 99: 11902-11907.
    CrossrefPubMedGoogle Scholar
  • 43 Fateh-Moghadam S, Htun P, Tomandl B. et al. Hyperresponsiveness of platelets in ischemic stroke. Thromb Haemost 2007; 97: 974-978.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Gertz SD, Wajnberg RS, Kurgan A. et al. Effect of magnesium sulfate on thrombus formation following partial arterial constriction: implications for coronary vasospasm. Magnesium 1987; 6: 225-235.
    PubMedGoogle Scholar
  • 45 Cruz MA, Handin RI, Wise RJ. The interaction of the von Willebrand factor-A1 domain with platelet glycoprotein Ib/IX. The role of glycosylation and disulfide bonding in a monomeric recombinant A1 domain protein. J Biol Chem 1993; 268: 21238-21245.
    PubMedGoogle Scholar
  • 46 Cruz MA, Yuan H, Lee JR. et al. Interaction of the von Willebrand factor (vWF) with collagen. Localization of the primary collagen-binding site by analysis of recombinant vWF a domain polypeptides. J Biol Chem 1995; 270: 10822-10827.
    CrossrefPubMedGoogle Scholar
  • 47 Hinshelwood J, Perkins SJ. Metal-dependent conformational changes in a recombinant vWF-A domain from human factor B: a solution study by circular dichroism, fourier transform infrared and (1)H NMR spectroscopy. J Mol Biol 2000; 298: 135-147.
    CrossrefPubMedGoogle Scholar
  • 48 Choi H, Aboulfatova K, Pownall HJ. et al. Shear-induced disulfide bond formation regulates adhesion activity of von willebrand factor. J Biol Chem 2007; 282: 35604-35611.
    CrossrefPubMedGoogle Scholar
  • 49 Savage B, Sixma JJ, Ruggeri ZM. Functional selfassociation of von Willebrand factor during platelet adhesion under flow. Proc Natl Acad Sci USA 2002; 99: 425-430.
    CrossrefPubMedGoogle Scholar
  • 50 Henrita v Z, Saelman EU, Schut-Hese KM. et al. Platelet adhesion to collagen type IV under flow conditions. Blood 1996; 88: 3862-3871.
    PubMedGoogle Scholar