Volume 34, Issue 6 pp. 1135-1148
Original Article
Free Access

Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver

Mark A. Ross

Mark A. Ross

Department of Cell Biology and Physiology and the Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA

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Christina M. Sander

Christina M. Sander

Department of Cell Biology and Physiology and the Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA

Department of Bioengineering and Biology, University of Pittsburgh, PA

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Talia B. Kleeb

Talia B. Kleeb

Department of Cell Biology and Physiology and the Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA

Department of Biology, Penn State University, State College, PA.

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Simon C. Watkins

Simon C. Watkins

Department of Cell Biology and Physiology and the Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA

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Donna Beer Stolz

Corresponding Author

Donna Beer Stolz

Department of Cell Biology and Physiology and the Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA

Cell Biology and Physiology, BST South 221, University of Pittsburgh Medical School, Pittsburgh, PA 15261. fax 412-648-8330===Search for more papers by this author
First published: 30 December 2003
Citations: 131

Abstract

Regenerating liver was evaluated for the spatiotemporal expression of angiogenic growth factor receptors on endothelial cell (EC) membranes during revascularization resulting from 70% partial hepatectomy (PHx). Fractions enriched in EC membranes were examined by Western blot for angiogenic growth factor receptor expression from 1 to 14 days after PHx. Increases in vascular endothelial growth factor (VEGF) receptors Flt-1 and Flk-1/KDR, angiopoietin receptors Tie-1, Tie-2, and platelet-derived growth factor receptor beta (PDGF-Rβ), modest increases in epidermal growth factor receptor (EGF-R), and no increase in hepatocyte growth factor receptor (c-Met) or fibroblast growth factor receptors (FGF-R) were observed in isolated membranes during EC proliferation. All receptors were tyrosine phosphorylated, and therefore activated, during peak expression. Immunofluorescence staining of regenerating liver identified populations with increased receptor expression, indicating cells receptive to ligand signaling. EGF-R was upregulated evenly throughout the sinusoidal membrane, whereas c-Met was observed on hepatocyte canaliculae, bile duct epithelium, and large vessel EC. Tie-2 and PDGF-Rβ were increased on sinusoidal and large vessel EC, whereas Tie-1 was expressed in EC surrounding avascular hepatic islands. Flk-1/KDR was increased on large vessels with slight increases on sinusoidal EC, whereas Flt-1 was increased in arterioles, sinusoidal EC as well as in hepatocytes. Although Flt-1 was phosphorylated on isolated hepatocytes, vascular endothelial growth factor165 (VEGF165) did not induce a proliferative or motogenic response. Proliferation assays on isolated EC indicated responsiveness to VEGF165, but synergism among several growth factors including PDGF-BB was also observed. The data identify novel autocrine and paracrine interactions and indicate that each growth factor acts on a specific set of EC at specific times during revascularization of regenerating liver.

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