Regular Article
Thrombospondin-1 Is Elevated with both Intimal Hyperplasia and Hypercholesterolemia

Presented at the Annual Symposium of the Association of Veterans Administration Surgeons, Louisville, Kentucky, May 5–7, 1997
https://doi.org/10.1006/jsre.1997.5209Get rights and content

Abstract

Background.Thrombospondin-1 (TSP-1) is important in platelet adhesion and aggregation, inflammation, cell to cell interaction, angiogenesis, and smooth muscle cell (SMC) proliferation. TSP-1 expression increases rapidly with injury. Therefore, we hypothesize that TSP-1 may play a role in the development of intimal hyperplasia (IH). The purpose of this study is to examine the interaction between cholesterol and TSP-1 on SMC proliferation and to quantitatively assess TSP-1 expression in an established model of IH, with and without underlying cholesterol-induced atherosclerosis.

Materials and methods. In vitro,rabbit aortic SMC culture studies were performed to see the effect of TSP-1 antibodies on PDGF and, separately, cholesterol-induced SMC proliferation.In vivo,23 rabbits were fed either a regular or a high-cholesterol diet. Hypercholesterolemia was confirmed by measurement of serum levels. Subsets underwent intraluminal aortic injury. Aortas were harvested 8–10 weeks later. Arterial wall TSP-1 was evaluated immunohistochemically and quantified by computer image analysis.

Results. In vitro,TSP-1 antibodies were able to inhibit PDGF and cholesterol-induced SMC proliferation (P< 0.05).In vivo,TSP-1 was found predominantly in the extracellular matrix in the rabbit aorta. IH was uniformly seen status-post angioplasty. Hyperplasia was more prominent in samples from hypercholesterolemic animals. ANOVA and Student'sttest analyses demonstrated significantly more TSP-1 in the high-cholesterol/angioplasty group than in all other groups (P= 0.0006 vs regular diet/no angioplasty group).

Conclusions.These data are consistent with the hypothesis that TSP-1 contributes to the development of IH. This study suggests that injured arteries in hypercholesterolemic atherosclerotic rabbits overexpress TSP-1.

References (40)

  • D.R. Bowen-Pope et al.

    Locally acting growth factors for vascular smooth muscle cells: Endogenous synthesis and release from platelets

    Circulation

    (1985)
  • A.W. Clowes et al.

    Mechanisms of stenosis after arterial injury

    Lab. Invest.

    (1983)
  • N.L. Baenziger et al.

    Thrombin sensitive protein of human platelet membranes

    Proc. Natl. Acad. Sci. USA

    (1971)
  • R.A. Majack et al.

    Platelet-derived growth factor and heparin-like glycosaminoglycans regulate thrombospondin synthesis and deposition in the matrix by smooth muscle cells

    J. Cell. Biol.

    (1985)
  • P. Clezardin

    Expression of thrombospondin by cells in culture

    Thrombospondin

    (1993)
  • G.P. Tuszynski et al.

    Thrombospondin promotes cell substratum adhesion

    Science

    (1987)
  • R.A. Majack et al.

    Cell surface thrombospondin is functionally essential for vascular smooth muscle cell proliferation

    J. Cell. Biol.

    (1988)
  • G. Taraboletti et al.

    Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: A potential angiogenesis regulatory factor

    J. Cell. Biol.

    (1990)
  • M. Miano et al.

    Smooth muscle cell immediate-early gene and growth factor activation follows vascular injury: A putative in vivo mechanism for autocrine growth

    Arterioscler. Thromb.

    (1993)
  • Cited by (83)

    • Fluvastatin inhibits intimal hyperplasia in wild-type but not Thbs1-null mice

      2017, Journal of Surgical Research
      Citation Excerpt :

      TSP-1 normally has a low plasma concentration and is not part of the normal arterial architecture21; however, in pathologic states such as PAD, the plasma levels of TSP-1 become elevated.12 Evidence that TSP-1 is a regulator of the acute response to arterial injury and vascular remodeling is that TSP-1 is (1) immediately abundant at sites of platelet activation (TSP-1 constitutes 25% of protein released by α granules), (2) a major biosynthetic product of associated cells (e.g., fibroblasts, macrophages, endothelial cells, platelet-derived growth factor–stimulated VSMCs), and (3) expressed in the arterial wall containing atherosclerotic plaque, after acute arterial injury and in early IH lesions.3,21-26 Consistent with the present work, several prior studies have demonstrated a functional significance for TSP-1 in IH development after arterial injury using different TSP-1 blocking strategies.

    View all citing articles on Scopus

    J. Lahav

    View full text