Glucose-Induced Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase-Dependent Upregulation of the Platelet-Derived Growth Factor-β Receptor Potentiates Vascular Smooth Muscle Cell Chemotaxis

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 2; pp. 519 - 526
• Main Authors: CAMPBELL, Malcolm, ALLEN, William E, SILVERSIDES, Jonathan A, TRIMBLE, Elisabeth R
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2003
• Subjects: Androstadienes - pharmacology; Animals; Aorta - physiology; Aorta, Thoracic; Associated diseases and complications; Biological and medical sciences; Blood circulation disorders; Chemotaxis; Chemotaxis - physiology; Chromones - pharmacology; Complications and side effects; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glucose - pharmacology; Humans; Medical sciences; Mitogen-Activated Protein Kinases - metabolism; Morpholines - pharmacology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Physiological aspects; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptor, Platelet-Derived Growth Factor beta - genetics; Reverse Transcriptase Polymerase Chain Reaction; Swine; Vascular diseases; Vascular smooth muscle; Wortmannin; Endocrinopathy; Phosphatidylinositol; Enzyme; Kinase; Transferases; Diabetes mellitus; Mitogen-activated protein kinase; Cardiovascular disease; Smooth muscle; Glucose; Chemotaxis; Platelet derived growth factor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.2.519

Glucose-Induced Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase-Dependent Upregulation of the Platelet-Derived Growth Factor-β Receptor Potentiates Vascular Smooth Muscle Cell Chemotaxis Malcolm Campbell 1 , William E. Allen 1 , Jonathan A. Silversides 1 and Elisabeth R. Trimble 1 2 1 Department of Clinical Biochemistry, Queen’s University, Belfast, U.K 2 The Royal Group of Hospitals, Belfast, U.K Abstract The aim of this study was to investigate the effects of elevated d -glucose concentrations on vascular smooth muscle cell (VSMC) expression of the platelet-derived growth factor (PDGF)β receptor and VSMC migratory behavior. Immunoprecipitation, immunofluorescent staining, and RT-PCR of human VSMCs showed that elevated d -glucose induced an increase in the PDGFβ receptor that was inhibited by phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathway inhibitors. Exposure to 25 mmol/l d -glucose (HG) induced increased phosphorylation of protein kinase B (PKB) and extracellular-regulated kinase (ERK). All HG chemotaxis assays (with either 10 days’ preincubation in HG or no preincubation) in a FCS or PDGF-BB gradient showed positive chemotaxis, whereas those in 5 mmol/l d -glucose did not. Assays were also run with concentrations ranging from 5 to 25 mmol/l d -glucose. Chemotaxis was induced at concentrations ≥9 mmol/l d -glucose. An anti-PDGFβ receptor antibody inhibited glucose-potentiated VSMC chemotaxis, as did the inhibitors for the PI3K and MAPK pathways. This study has shown that small increases in d -glucose concentration, for a short period, increase VSMC expression of the PDGFβ receptor and VSMC sensitivity to chemotactic factors in serum, leading to altered migratory behavior in vitro. It is probable that similar processes occur in vivo with glucose-enhanced chemotaxis of VSMCs, operating through PDGFβ receptor-operated pathways, contributing to the accelerated formation of atheroma in diabetes. Footnotes Address correspondence and reprint requests to Dr. W.E. Allen, Department of Clinical Biochemistry, Queen’s University, Belfast Institute of Clinical Science, Grosvenor Road, Belfast BT12 6BJ, U.K. E-mail: w.allen{at}qub.ac.uk . Received for publication 18 April 2002 and accepted in revised form 4 November 2002. M.C. and W.E.A. contributed equally to this study. CSF, colony-stimulating factor; ERK, extracellular-regulated kinase; HRP, horseradish peroxidase; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; TRITC, tetramethyl rhodamine isothiocyanate; VSMC, vascular smooth muscle cell. DIABETES