Tissue plasminogen activator increases canine endothelial cell proliferation rate through a plasmin-independent, receptor-mediated mechanism

被引:31
作者
Welling, TH
Huber, TS
Messina, LM
Stanley, JC
机构
[1] Section of Vascular Surgery, Department of Surgery, Univ. of Michigan Medical School, Ann Arbor
关键词
D O I
10.1006/jsre.1996.0369
中图分类号
R61 [外科手术学];
学科分类号
摘要
Background: Tissue plasminogen activator (tPA) is elevated in cancer patients and is thought to promote tumor angiogenesis by facilitating endothelial cell. migration through plasmin-mediated degradation of extracellular matrix. Due to the presence of an epidermal growth factor (EGF)-finger domain in the tPA A-chain and the existence of an endothelial cell (EC) receptor that binds this domain, it was hypothesized that tPA has a direct receptor-mediated effect on EC proliferation, independent of plasmin. Methods and Results: Using cultured canine ECs, tPA (7.25 mu g/ml, similar to 107 nM) increased proliferation as much as 50 and 170% in the absence and presence of growth factors, respectively. tPA-induced increases in EC proliferation occurred independent of plasmin generation, as the plasmin inhibitor, aprotinin (10 mu g/ml) did not inhibit tPA-induced proliferation. However, tPA-induced proliferation was inhibited dose-dependently to a maximum of 78% using a monoclonal antibody against the tPA EGF-finger domain. This antibody, known to inhibit tPA binding to its receptor, did not inhibit tPA-induced plasmin generation. To investigate the role of potential signal transduction pathways, ECs were exposed to lavendustin A, a tyrosine kinase inhibitor, at 33.5 mu M (IC50 for basic fibroblast growth factor). Lavendustin A did not inhibit tPA-induced EC proliferation. However, Rp-cAMP, an inhibitor of cAMP-dependent kinases, specifically inhibited tPA-induced EC proliferation in a dose-dependent manner (IC50 = 50.5 mu m). Pertussis toxin at maximal concentrations for this system (0.5 ng/ml) did not inhibit tPA-induced EC proliferation. Conclusion: These results lend support to the hypothesis that tPA may have a direct receptor-mediated effect on EC proliferation and that this effect occurs independent of plasmin and may be dependent upon protein kinase A activity. (C) 1996 Academic Press, Inc.
引用
收藏
页码:36 / 42
页数:7
相关论文
共 50 条
  • [1] TISSUE PLASMINOGEN-ACTIVATOR - CHEMICAL AND PHYSIOLOGICAL-ASPECTS
    BACHMANN, F
    KRUITHOF, IEKO
    [J]. SEMINARS IN THROMBOSIS AND HEMOSTASIS, 1984, 10 (01) : 6 - 17
  • [2] COMMON EVOLUTIONARY ORIGIN OF THE FIBRIN-BINDING STRUCTURES OF FIBRONECTIN AND TISSUE-TYPE PLASMINOGEN-ACTIVATOR
    BANYAI, L
    VARADI, A
    PATTHY, L
    [J]. FEBS LETTERS, 1983, 163 (01) : 37 - 41
  • [3] BARNATHAN ES, 1988, J BIOL CHEM, V263, P7792
  • [4] BASSELDUBY R, 1992, J BIOL CHEM, V267, P9668
  • [5] BEEBE DP, 1989, BLOOD, V74, P2034
  • [6] TUMOR INTERACTIONS WITH THE VASCULATURE - ANGIOGENESIS AND TUMOR-METASTASIS
    BLOOD, CH
    ZETTER, BR
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA, 1990, 1032 (01) : 89 - 118
  • [7] HEPARIN POTENTIATION OF 3T3-ADIPOCYTE STIMULATED ANGIOGENESIS - MECHANISMS OF ACTION ON ENDOTHELIAL-CELLS
    CASTELLOT, JJ
    KAMBE, AM
    DOBSON, DE
    SPIEGELMAN, BM
    [J]. JOURNAL OF CELLULAR PHYSIOLOGY, 1986, 127 (02) : 323 - 329
  • [8] PLASMINOGEN ACTIVATORS, TISSUE DEGRADATION, AND CANCER
    DANO, K
    ANDREASEN, PA
    GRONDAHLHANSEN, J
    KRISTENSEN, P
    NIELSEN, LS
    SKRIVER, L
    [J]. ADVANCES IN CANCER RESEARCH, 1985, 44 : 139 - 266
  • [9] DEVORE JL, 1991, PROBABILITY STAT ENG, P337
  • [10] INDUCTION OF ANGIOGENESIS DURING THE TRANSITION FROM HYPERPLASIA TO NEOPLASIA
    FOLKMAN, J
    WATSON, K
    INGBER, D
    HANAHAN, D
    [J]. NATURE, 1989, 339 (6219) : 58 - 61