Co-Authors:
Ankoma-Sey, V., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States, Division of Gastroenterology, Univ. of Texas at Houston Med. Sch., MSB 4.23, 6431 Fannin, Houston, TX 77030, United States
Matli, M., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States
Chang, K.B., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States
Lalazar, A., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States
Donner, D.B., Dept. of Physiology and Biophysics, Walther Oncology Center, University of Indiana, Indiapolis, IN, United States
Wong, L., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States
Warren, R.S., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States
Friedman, S.L., UCSF Liver Center, Departments of Medicine and Surgery, University of California, San Francisco, CA, United States, Box 1123, Division of Liver Diseases, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10029, United States
Abstract:
Homology PCR has been used to identify receptor tyrosine kinases (RTKs) expressed during activation of rat hepatic stellate cells, the key fibrogenic mesenchymal element in the liver. Partial cDNAs encoding several RTKs were cloned from stellate cells activated in vivo, including those of Flt-1, Flk-1, c-met, PDGFR, and Tyro10/DDR2. RNAse protection from cells activated in vivo demonstrated biphasic induction of flt-1 and flk-1 mRNAs, receptors for vascular endothelial growth factor (VEGF). Culture-activation of stellate cells was associated with increased [ 125I]VEGF binding and Flt-1 and Flk-1 receptor protein. Induction of VEGF binding sites correlated with an 2.5-fold increase in DNA synthesis in response to VEGF, but only if cells were activated by growth on collagen I, whereas cells maintained in a quiescent state on a basement membrane-like substratum (EHS matrix) were nonproliferative. In both stellate and endothelial cells VEGF-induced mitogenesis was augmented by co-incubation with basic fibroblast growth factor (bFGF), a cytokine with known synergy with VEGF. These findings suggest that the cellular targets of VEGF in liver may not be confined to sinusoidal endothelial cells, and that VEGF responses reflect combined effects on both hepatic stellate cells and sinusoidal endothelium.
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