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  • Title: Inhibition of phosphatidylinositol 3-kinase and protein kinase C attenuates extracellular matrix protein-induced vascular smooth muscle cell chemotaxis.
    Author: Willis AI, Fuse S, Wang XJ, Chen E, Tuszynski GP, Sumpio BE, Gahtan V.
    Journal: J Vasc Surg; 2000 Jun; 31(6):1160-7. PubMed ID: 10842153.
    Abstract:
    PURPOSE: Intimal hyperplasia (IH), a significant cause of vascular reconstructive failure, is characterized by abnormal vascular smooth muscle cell (VSMC) migration, proliferation, and extracellular matrix (ECM) deposition. The ECM proteins, thrombospondin-1 (TSP-1), fibronectin (Fn), and vitronectin (Vn) can induce VSMC migration; however, the cellular signaling pathways involved are not identical for each ECM protein. Phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) are two enzymes that have been associated with VSMC migration. We sought to elucidate the roles of these enzymes in TSP-1-, Fn-, and Vn-stimulated VSMC migration. METHODS: Chemotaxis assays were performed by using a modified Boyden Chamber. TSP-1, Fn, or Vn (20 microg/mL) or serum-free media (SFM) was placed in the bottom wells of the chamber. Quiescent bovine aortic VSMC were preincubated with LY 294002 (100 micromol/L), a PI3K inhibitor, bisindolylmaleimide I (GF 109203X, 1 micromol/L), a PKC inhibitor, or in SFM alone for 30 minutes. VSMCs (50,000 cells per well) were then placed in the top wells of the chamber, and the assay was conducted for 4 hours at 37 degrees C. Results were recorded as the number of cells migrated per five fields (400x) and analyzed by means of the paired t test, with P value less than.05 considered to be significant (n = 3). RESULTS: The VSMC migration was significantly increased by TSP-1, Fn, and Vn. LY 294002 inhibited TSP-1-, Fn-, and Vn-stimulated VSMC migration (85% to 89%, P <.05). GF 109203X inhibited only TSP-1-stimulated migration (65%, P <.05). CONCLUSION: These results suggest that TSP-1-, Fn-, and Vn-stimulated migration is at least partially dependent on PI3K. However, only TSP-1 stimulated migration is at least partially dependent on PKC.
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