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J Clin Invest. 1993 February; 91(2): 547–552.
PMCID: PMC287977

Agonist-mediated tissue factor expression in cultured vascular smooth muscle cells. Role of Ca2+ mobilization and protein kinase C activation.


Tissue factor (TF) is a low molecular weight glycoprotein that initiates the clotting cascade and is considered to be a major regulator of coagulation, hemostasis, and thrombosis. TF is not expressed in the intima or media of normal adult blood vessels. Accordingly, it has been hypothesized that the initiation of intravascular coagulation may require the "induced" expression of TF in the vessel wall. We report that TF mRNA and protein are rapidly and markedly induced in early and late passaged vascular smooth muscle cells (VSMC) by growth factors (serum, platelet-derived growth factor, epidermal growth factor), vasoactive agonists (angiotensin II), and a clotting factor (alpha-thrombin). The induction of TF mRNA by these agents is dependent upon mobilization of intracellular Ca2+ and is blocked by Ca2+ chelation. In contrast to other growth factor-responsive genes, such as KC and c-fos, downregulation of protein kinase C activity by prolonged treatment with phorbol esters fails to block agonist-mediated TF induction. This raises the possibility that protein kinase C activation may not be necessary for TF mRNA induction in VSMC. VSMC may play a role in the generation or propagation of thrombus through the induction of TF, particularly in settings, such as those associated with acute vessel injury, where the endothelium is denuded and the VSMC are exposed to circulating blood.

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  • Nemerson Y. Tissue factor and hemostasis. Blood. 1988 Jan;71(1):1–8. [PubMed]
  • Edgington TS, Mackman N, Brand K, Ruf W. The structural biology of expression and function of tissue factor. Thromb Haemost. 1991 Jul 12;66(1):67–79. [PubMed]
  • Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989 May;134(5):1087–1097. [PubMed]
  • Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2839–2843. [PubMed]
  • Weiss HJ, Turitto VT, Baumgartner HR, Nemerson Y, Hoffmann T. Evidence for the presence of tissue factor activity on subendothelium. Blood. 1989 Mar;73(4):968–975. [PubMed]
  • Scarpati EM, Sadler JE. Regulation of endothelial cell coagulant properties. Modulation of tissue factor, plasminogen activator inhibitors, and thrombomodulin by phorbol 12-myristate 13-acetate and tumor necrosis factor. J Biol Chem. 1989 Dec 5;264(34):20705–20713. [PubMed]
  • Crossman DC, Carr DP, Tuddenham EG, Pearson JD, McVey JH. The regulation of tissue factor mRNA in human endothelial cells in response to endotoxin or phorbol ester. J Biol Chem. 1990 Jun 15;265(17):9782–9787. [PubMed]
  • Lyberg T, Galdal KS, Evensen SA, Prydz H. Cellular cooperation in endothelial cell thromboplastin synthesis. Br J Haematol. 1983 Jan;53(1):85–95. [PubMed]
  • Conway EM, Bach R, Rosenberg RD, Konigsberg WH. Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells. Thromb Res. 1989 Feb 1;53(3):231–241. [PubMed]
  • Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest. 1987 Jan;79(1):124–130. [PMC free article] [PubMed]
  • Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986 Mar 1;163(3):740–745. [PMC free article] [PubMed]
  • Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone MA., Jr Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med. 1984 Aug 1;160(2):618–623. [PMC free article] [PubMed]
  • Nawroth PP, Handley DA, Esmon CT, Stern DM. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci U S A. 1986 May;83(10):3460–3464. [PubMed]
  • Brox JH, Osterud B, Bjørklid E, Fenton JW., 2nd Production and availability of thromboplastin in endothelial cells: the effects of thrombin, endotoxin and platelets. Br J Haematol. 1984 Jun;57(2):239–246. [PubMed]
  • Hartzell S, Ryder K, Lanahan A, Lau LF, Nathan D. A growth factor-responsive gene of murine BALB/c 3T3 cells encodes a protein homologous to human tissue factor. Mol Cell Biol. 1989 Jun;9(6):2567–2573. [PMC free article] [PubMed]
  • Bloem LJ, Chen L, Konigsberg WH, Bach R. Serum stimulation of quiescent human fibroblasts induces the synthesis of tissue factor mRNA followed by the appearance of tissue factor antigen and procoagulant activity. J Cell Physiol. 1989 May;139(2):418–423. [PubMed]
  • Maynard JR, Dreyer BE, Stemerman MB, Pitlick FA. Tissue-factor coagulant activity of cultured human endothelial and smooth muscle cells and fibroblasts. Blood. 1977 Sep;50(3):387–396. [PubMed]
  • Travo P, Barrett G, Burnstock G. Differences in proliferation of primary cultures of vascular smooth muscle cells taken from male and female rats. Blood Vessels. 1980;17(2):110–116. [PubMed]
  • Taubman MB, Berk BC, Izumo S, Tsuda T, Alexander RW, Nadal-Ginard B. Angiotensin II induces c-fos mRNA in aortic smooth muscle. Role of Ca2+ mobilization and protein kinase C activation. J Biol Chem. 1989 Jan 5;264(1):526–530. [PubMed]
  • Berk BC, Taubman MB, Griendling KK, Cragoe EJ, Jr, Fenton JW, Brock TA. Thrombin-stimulated events in cultured vascular smooth-muscle cells. Biochem J. 1991 Mar 15;274(Pt 3):799–805. [PubMed]
  • Berk BC, Brock TA, Gimbrone MA, Jr, Alexander RW. Early agonist-mediated ionic events in cultured vascular smooth muscle cells. Calcium mobilization is associated with intracellular acidification. J Biol Chem. 1987 Apr 15;262(11):5065–5072. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Taubman MB, Rollins BJ, Poon M, Marmur J, Green RS, Berk BC, Nadal-Ginard B. JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells. Circ Res. 1992 Feb;70(2):314–325. [PubMed]
  • Taubman MB, Grant JW, Nadal-Ginard B. Cloning and characterization of mammalian myosin regulatory light chain (RLC) cDNA: the RLC gene is expressed in smooth, sarcomeric, and nonmuscle tissues. J Cell Biol. 1987 Jun;104(6):1505–1513. [PMC free article] [PubMed]
  • Nemerson Y. The phospholipid requirement of tissue factor in blood coagulation. J Clin Invest. 1968 Jan;47(1):72–80. [PMC free article] [PubMed]
  • Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell. 1986 Jul 18;46(2):155–169. [PubMed]
  • Coughlin SR, Lee WM, Williams PW, Giels GM, Williams LT. c-myc gene expression is stimulated by agents that activate protein kinase C and does not account for the mitogenic effect of PDGF. Cell. 1985 Nov;43(1):243–251. [PubMed]
  • Tsuda T, Hamamori Y, Yamashita T, Fukumoto Y, Takai Y. Involvement of three intracellular messenger systems, protein kinase C, calcium ion and cyclic AMP, in the regulation of c-fos gene expression in Swiss 3T3 cells. FEBS Lett. 1986 Nov 10;208(1):39–42. [PubMed]
  • Chamley-Campbell J, Campbell GR, Ross R. The smooth muscle cell in culture. Physiol Rev. 1979 Jan;59(1):1–61. [PubMed]
  • Chamley-Campbell JH, Campbell GR, Ross R. Phenotype-dependent response of cultured aortic smooth muscle to serum mitogens. J Cell Biol. 1981 May;89(2):379–383. [PMC free article] [PubMed]
  • Kocher O, Gabbiani G. Analysis of alpha-smooth-muscle actin mRNA expression in rat aortic smooth-muscle cells using a specific cDNA probe. Differentiation. 1987;34(3):201–209. [PubMed]
  • Rozengurt E, Sinnett-Smith JW. Bombesin induction of c-fos and c-myc proto-oncogenes in Swiss 3T3 cells: significance for the mitogenic response. J Cell Physiol. 1987 May;131(2):218–225. [PubMed]
  • Bach R, Rifkin DB. Expression of tissue factor procoagulant activity: regulation by cytosolic calcium. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6995–6999. [PubMed]
  • Callahan KS, Blumenthal DK, Fair DS. Tissue factor expression in human endothelial cells is regulated by calcium/calmodulin. Adv Second Messenger Phosphoprotein Res. 1990;24:449–454. [PubMed]
  • Nawroth PP, Stern DM, Kisiel W, Bach R. Cellular requirements for tissue factor generation by bovine aortic endothelial cells in culture. Thromb Res. 1985 Dec 1;40(5):677–691. [PubMed]
  • Schorer AE, Kaplan ME, Rao GH, Moldow CF. Interleukin 1 stimulates endothelial cell tissue factor production and expression by a prostaglandin-independent mechanism. Thromb Haemost. 1986 Dec 15;56(3):256–259. [PubMed]
  • Ase K, Berry N, Kikkawa U, Kishimoto A, Nishizuka Y. Differential down-regulation of protein kinase C subspecies in KM3 cells. FEBS Lett. 1988 Aug 29;236(2):396–400. [PubMed]
  • Pettersen KS, Wiiger MT, Narahara N, Andoh K, Gaudernack G, Prydz H. Induction of tissue factor synthesis in human umbilical vein endothelial cells involves protein kinase C. Thromb Haemost. 1992 Apr 2;67(4):473–477. [PubMed]
  • Steele PM, Chesebro JH, Stanson AW, Holmes DR, Jr, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res. 1985 Jul;57(1):105–112. [PubMed]
  • Clowes AW, Clowes MM, Fingerle J, Reidy MA. Regulation of smooth muscle cell growth in injured artery. J Cardiovasc Pharmacol. 1989;14 (Suppl 6):S12–S15. [PubMed]
  • Schwartz L, Bourassa MG, Lespérance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bonan R, David PR. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med. 1988 Jun 30;318(26):1714–1719. [PubMed]
  • Uchida Y, Hasegawa K, Kawamura K, Shibuya I. Angioscopic observation of the coronary luminal changes induced by percutaneous transluminal coronary angioplasty. Am Heart J. 1989 Apr;117(4):769–776. [PubMed]
  • Huang CL, Ives HE. Growth inhibition by protein kinase C late in mitogenesis. Nature. 329(6142):849–850. [PubMed]

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