Differential effects of imatinib on PDGF‐induced proliferation and PDGF receptor signaling in human arterial and venous smooth muscle cells

Platelet‐derived growth factor (PDGF) has been implicated in smooth muscle cell (SMC) proliferation, a key event in the development of myointimal hyperplasia in vascular grafts. Recent evidence suggests that the PDGF receptor (PDGFR) tyrosine kinase inhibitor, imatinib, can prevent arterial proliferative diseases. Because hyperplasia is far more common at the venous anastomosis than the arterial anastomosis in vascular grafts, we investigated whether imatinib also inhibited venous SMC (VSMC) proliferation, and examined possible differences in its mechanism of action between VSMC and arterial SMC (ASMC). Human ASMC and VSMC were stimulated with PDGF‐AB, in the presence or absence of imatinib (0.1–10 µM). Proliferation was assayed using the 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation assay, while PDGFR, Akt and ERK1/2‐mitogen activated protein kinase (MAPK) signaling pathways were investigated by immunoblotting. The proliferative response to PDGF at 50 and 100 ng/ml was 32 and 43% greater, respectively, in VSMC than in ASMC. Similarly, PDGF‐stimulated proliferation was more sensitive to inhibition by imatinib in VSMC than ASMC (IC50 = 0.05 µM vs. 0.4 µM; P < 0.01). Imatinib also more effectively inhibited PDGF‐induced phosphorylation of PDGFRβ and Akt in VSMC, compared to ASMC. These data highlight inherent pharmacodynamic differences between VSMC and ASMC in receptor and cell signaling functions and suggest that imatinib therapy may be useful for the prevention of venous stenosis in vascular grafts. J. Cell. Biochem. 99: 1553–1563, 2006. © 2006 Wiley‐Liss, Inc.

[1]  B. Strauss,et al.  In vitro differences between venous and arterial-derived smooth muscle cells: potential modulatory role of decorin. , 2005, Cardiovascular research.

[2]  J. Wood,et al.  Combined Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor Inhibition in Rat Cardiac Allografts: Beneficial Effects on Inflammation and Smooth Muscle Cell Proliferation , 2005, Transplantation.

[3]  B. Vanhaesebroeck,et al.  Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways , 2004, Circulation research.

[4]  Lina Souan,et al.  Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. , 2004, Blood.

[5]  K. Kent,et al.  The role of phospholipase C and phosphatidylinositol 3-kinase in vascular smooth muscle cell migration and proliferation. , 2004, The Journal of surgical research.

[6]  M. Englesbe,et al.  Concomitant blockade of platelet-derived growth factor receptors α and β induces intimal atrophy in baboon PTFE grafts , 2004 .

[7]  S. Epstein,et al.  Akt Controls Vascular Smooth Muscle Cell Proliferation In Vitro and In Vivo by Delaying G1/S Exit , 2003, Circulation research.

[8]  H. Friess,et al.  Effects of STI571 (gleevec) on pancreatic cancer cell growth , 2003, Molecular Cancer.

[9]  Joseph Khoury,et al.  Signaling through PI3K/Akt mediates stretch and PDGF-BB-dependent DNA synthesis in bladder smooth muscle cells. , 2003, The Journal of urology.

[10]  T. Nakao,et al.  Role of JNK, p38, and ERK in Platelet-Derived Growth Factor–Induced Vascular Proliferation, Migration, and Gene Expression , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[11]  Richard G. W. Anderson,et al.  LRP: Role in Vascular Wall Integrity and Protection from Atherosclerosis , 2003, Science.

[12]  A. Narayana,et al.  Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis. , 2002, Kidney international.

[13]  Michael Fisher,et al.  Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty. , 2002, Cardiovascular research.

[14]  Y. Ouchi,et al.  Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways , 2002, Circulation.

[15]  B. Druker,et al.  STI571 (Gleevec) as a paradigm for cancer therapy. , 2002, Trends in molecular medicine.

[16]  J. Hoidal,et al.  NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[17]  B. Druker,et al.  Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  M Cascante,et al.  Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. , 2001, The Journal of biological chemistry.

[19]  Y. Kaneda,et al.  Gene Transfer of Dominant-Negative Mutants of Extracellular Signal-Regulated Kinase and c-Jun NH2-Terminal Kinase Prevents Neointimal Formation in Balloon-Injured Rat Artery , 2001, Circulation research.

[20]  S. Heffelfinger,et al.  Venous neointimal hyperplasia in polytetrafluoroethylene dialysis grafts. , 2001, Kidney international.

[21]  R. Atkins,et al.  PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis. , 2001, Kidney international.

[22]  R. Salgia,et al.  Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571 , 2000, Oncogene.

[23]  S. Meloche,et al.  Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms. , 2000, The Journal of cell biology.

[24]  S Stefoni,et al.  PDGF-AB release during and after haemodialysis procedure. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[25]  P. Waybill,et al.  Arterial and venous smooth muscle cell proliferation in response to co-culture with arterial and venous endothelial cells. , 1999, Journal of vascular and interventional radiology : JVIR.

[26]  E. Krebs,et al.  Crosstalk between protein kinase A and growth factor receptor signaling pathways in arterial smooth muscle. , 1999, Cellular signalling.

[27]  E. Buchdunger,et al.  Selective Tyrosine Kinase Inhibitor for the Platelet-Derived Growth Factor Receptor In Vitro Inhibits Smooth Muscle Cell Proliferation After Reinjury of Arterial Intima In Vivo , 1999, Cardiovascular Drugs and Therapy.

[28]  M. Davies,et al.  Alterations in wall tension and shear stress modulate tyrosine kinase signaling and wall remodeling in experimental vein grafts. , 1999, Journal of vascular surgery.

[29]  C. Heldin,et al.  Mechanism of action and in vivo role of platelet-derived growth factor. , 1999, Physiological reviews.

[30]  G. Regolisti,et al.  Increased plasma levels of platelet-derived growth factor (PDGF-BB + PDGF-AB) in patients with never-treated mild essential hypertension. , 1998, American journal of hypertension.

[31]  S Q Liu,et al.  Prevention of focal intimal hyperplasia in rat vein grafts by using a tissue engineering approach. , 1998, Atherosclerosis.

[32]  T. Lüscher,et al.  Different proliferative properties of smooth muscle cells of human arterial and venous bypass vessels: role of PDGF receptors, mitogen-activated protein kinase, and cyclin-dependent kinase inhibitors. , 1998, Circulation.

[33]  E. Buchdunger,et al.  Inhibition of platelet‐derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  E. Edelman,et al.  Antisense oligonucleotide inhibition of PDGFR-beta receptor subunit expression directs suppression of intimal thickening. , 1997, Circulation.

[35]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[36]  G. E. Green,et al.  Coronary bypass surgery with internal-thoracic-artery grafts--effects on survival over a 15-year period. , 1996, The New England journal of medicine.

[37]  Andrius Kazlauskas,et al.  The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase , 1995, Cell.

[38]  E. Nabel,et al.  Recombinant platelet-derived growth factor B gene expression in porcine arteries induce intimal hyperplasia in vivo. , 1993, The Journal of clinical investigation.

[39]  M. Englesbe,et al.  Concomitant blockade of platelet-derived growth factor receptors alpha and beta induces intimal atrophy in baboon PTFE grafts. , 2004, Journal of vascular surgery.