Molecular and Cellular Biochemistry

, Volume 410, Issue 1–2, pp 85–91 | Cite as

Dyslipidemia regulates thrombospondin-1-induced vascular smooth muscle cell chemotaxis

  • Pratik Desai
  • Jeffrey J. Stein
  • Sufyan A. Siddiqui
  • Kristopher G. Maier
  • Vivian Gahtan


Dyslipidemia is a risk factor for intimal hyperplasia (IH). Key to IH is vascular smooth muscle cell (VSMC) migration. Thrombospondin-1 (TSP-1) is a matricellular protein that stimulates VSMC migration. Hypothesis: HDL will inhibit and LDL will augment TSP-1-induced VSMC chemotaxis. VSMC chemotaxis will be inhibited by the HDL moiety, S1P, through the S1PR1 receptor, and augmented by the LDL component, LPA, through the LPAR1 receptor. The goal of this study was to determine the effect of HDL and LDL and their receptors on TSP-1-induced VSMC chemotaxis. For VSMC chemotaxis to TSP-1 cells received the following pretreatments: low (25 µg/ml) or optimal (75 µg/ml) concentration of HDL, S1P, optimal (75 µg/ml) or high (175 µg/ml) concentration of LDL, or LPA. For the receptor studies, VSMCs were transfected with siRNA to S1PR1, S1PR3, LPAR1, LPAR2, LPAR3, or a S1PR2 receptor antagonist. The TSP-1-induced chemotaxis results were (1) HDL (25 µg/ml) or LDL (75 µg/ml) exhibited no effect on chemotaxis; (2) HDL (75 µg/ml) inhibited chemotaxis by 50.9 ± 8 % and S1P by 43.4 ± 11.6 %; (3) LDL (175 µg/ml) augmented chemotaxis by 30 ± 10.4 % and LPA by 25.6 ± 12.3 %; (4) S1PR1 and S1PR3 knockdown and S1PR2 antagonist-treated cells augmented chemotaxis; and (5) LPAR1 and LPAR2 knockdown inhibited and LPAR3 knockdown had no effect on chemotaxis. In conclusion, HDL/S1P inhibits, while LDL/LPA stimulates TSP-1-induced VSMC chemotaxis. The HDL/S1P effect is mediated by the S1PR1-3 receptors. The LDL/LPA effects are mediated by the LPAR1 and LPAR2 receptors, but not LPAR3. Therefore, lipids have significant effects on TSP-1-induced VSMC chemotaxis.


Thrombospondin-1 Muscle Smooth Chemotaxis Dyslipidemia Lipoproteins 



Supported by Veteran’s Affairs Merit Grant # BX001243.

Compliance with ethical standards

Conflict of Interest

There are no conflicts of interest to report.


  1. 1.
    Stevens SL, Hilgarth K, Ryan US, Trachtenberg J, Choi E, Callow AD (1992) The synergistic effect of hypercholesterolemia and mechanical injury on intimal hyperplasia. Ann Vasc Surg 6(1):55–61CrossRefPubMedGoogle Scholar
  2. 2.
    Smith DG (2007) Epidemiology of dyslipidemia and economic burden on the healthcare system. Am J Manag Care 13(Suppl 3):S68–S71PubMedGoogle Scholar
  3. 3.
    Johnson ML, Pietz K, Battleman DS, Beyth RJ (2004) Prevalence of comorbid hypertension and dyslipidemia and associated cardiovascular disease. Am J Manag Care 10(12):926–932PubMedGoogle Scholar
  4. 4.
    Vinals M, Martinez-Gonzalez J, Badimon JJ, Badimon L (1997) HDL-induced prostacyclin release in smooth muscle cells is dependent on cyclooxygenase-2 (Cox-2). Arterioscler Thromb Vasc Biol 17(12):3481–3488CrossRefPubMedGoogle Scholar
  5. 5.
    Muto A, Fitzgerald TN, Pimiento JM, Maloney SP, Teso D, Paszkowiak JJ, Westvik TS, Kudo FA, Nishibe T, Dardik A (2007) Smooth muscle cell signal transduction: implications of vascular biology for vascular surgeons. J Vasc Surg 45(Suppl A):A15–A24CrossRefPubMedGoogle Scholar
  6. 6.
    Rodriguez C, Gonzalez-Diez M, Badimon L, Martinez-Gonzalez J (2009) Sphingosine-1-phosphate: a bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb Haemost 101(4):665–673PubMedGoogle Scholar
  7. 7.
    Damirin A, Tomura H, Komachi M, Liu JP, Mogi C, Tobo M, Wang JQ, Kimura T, Kuwabara A, Yamazaki Y, Ohta H, Im DS, Sato K, Okajima F (2007) Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells. Am J Physiol 292(5):H2513–H2522Google Scholar
  8. 8.
    Takuwa Y, Takuwa N, Sugimoto N (2002) The Edg family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities. J Biochem 131(6):767–771CrossRefPubMedGoogle Scholar
  9. 9.
    Blaho VA, Hla T (2011) Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors. Chem Rev 111(10):6299–6320. doi: 10.1021/cr200273u PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Booth WJ, Berndt MC (1987) Thrombospondin in clinical disease states. Semin Thromb Hemost 13(3):298–306CrossRefPubMedGoogle Scholar
  11. 11.
    Chen D, Asahara T, Krasinski K, Witzenbichler B, Yang J, Magner M, Kearney M, Frazier WA, Isner JM, Andres V (1999) Antibody blockade of thrombospondin accelerates reendothelialization and reduces neointima formation in balloon-injured rat carotid artery. Circulation 100(8):849–854CrossRefPubMedGoogle Scholar
  12. 12.
    Chen H, Herndon ME, Lawler J (2000) The cell biology of thrombospondin-1. Matrix Biol 19(7):597–614CrossRefPubMedGoogle Scholar
  13. 13.
    Roth JJ, Gahtan V, Brown JL, Gerhard C, Swami VK, Rothman VL, Tulenko TN, Tuszynski GP (1998) Thrombospondin-1 is elevated with both intimal hyperplasia and hypercholesterolemia. J Surg Res 74(1):11–16CrossRefPubMedGoogle Scholar
  14. 14.
    Miyauchi K, Kasai T, Yokayama T, Aihara K, Kurata T, Kajimoto K, Okazaki S, Ishiyama H, Daida H (2008) Effectiveness of statin-eluting stent on early inflammatory response and neointimal thickness in a porcine coronary model. Circ J 72(5):832–838CrossRefPubMedGoogle Scholar
  15. 15.
    Tamama K, Tomura H, Sato K, Malchinkhuu E, Damirin A, Kimura T, Kuwabara A, Murakami M, Okajima F (2005) High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component. Atherosclerosis 178(1):19–23CrossRefPubMedGoogle Scholar
  16. 16.
    Duru EA, Fu Y, Davies MG (2012) Role of S-1-P receptors and human vascular smooth muscle cell migration in diabetes and metabolic syndrome. J Surg Res 177(2):e75–e82. doi: 10.1016/j.jss.2011.12.012 PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Mutoh T, Rivera R, Chun J (2012) Insights into the pharmacological relevance of lysophospholipid receptors. Br J Pharmacol 165(4):829–844. doi: 10.1111/j.1476-5381.2011.01622.x PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Takuwa Y, Okamoto Y, Yoshioka K, Takuwa N (2008) Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system. Biochim Biophys Acta 1781(9):483–488. doi: 10.1016/j.bbalip.2008.04.003 CrossRefPubMedGoogle Scholar
  19. 19.
    Ryu Y, Takuwa N, Sugimoto N, Sakurada S, Usui S, Okamoto H, Matsui O, Takuwa Y (2002) Sphingosine-1-phosphate, a platelet-derived lysophospholipid mediator, negatively regulates cellular Rac activity and cell migration in vascular smooth muscle cells. Circ Res 90(3):325–332CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2015

Authors and Affiliations

  • Pratik Desai
    • 2
  • Jeffrey J. Stein
    • 1
    • 2
  • Sufyan A. Siddiqui
    • 1
  • Kristopher G. Maier
    • 1
    • 2
  • Vivian Gahtan
    • 1
    • 2
  1. 1.Department of SurgerySUNY Upstate Medical UniversitySyracuseUSA
  2. 2.Department of Veterans Affairs Healthcare Network Upstate New York at SyracuseSyracuseUSA

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