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(Circulation Research. 2006;98:36.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Differential Regulation of Hyaluronic Acid Synthase Isoforms in Human Saphenous Vein Smooth Muscle Cells

Possible Implications for Vein Graft Stenosis

M. van den Boom, M. Sarbia, K. von Wnuck Lipinski, P. Mann, J. Meyer-Kirchrath, B.H. Rauch, K. Grabitz, B. Levkau, K. Schrör, J.W. Fischer

From the Molekulare Pharmakologie (M.v.d.B., P.M., J.W.F.), Institut für Pharmakologie und Klinische Pharmakologie (J.M.-K., B.H.R., K.S.), Heinrich Heine Universität, Düsseldorf; Institut für Allgemeine Pathologie der Technischen Universität München (M.S.); Institut für Pathophysiologie (K.v.W.L., B.L.), Universitätsklinikum Essen; and Klinik für Gefäßchirurgie und Nierentransplantation (K.G.), Universitätsklinikum Düsseldorf, Germany.

Correspondence to Jens W. Fischer, Molecular Pharmacology, Institut für Pharmakologie and Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail jens.fischer{at}uni-duesseldorf.de

Autologous saphenous vein bypass grafts (SVG) are frequently compromised by neointimal thickening and subsequent atherosclerosis eventually leading to graft failure. Hyaluronic acid (HA) generated by smooth muscle cells (SMC) is thought to augment the progression of atherosclerosis. The aim of the present study was (1) to investigate HA accumulation in native and explanted arterialized SVG, (2) to identify factors that regulate HA synthase (HAS) expression and HA synthesis, and (3) to study the function of the HAS2 isoform. In native SVG, expression of all 3 HAS isoforms was detected by RT-PCR. Histochemistry revealed that native and arterialized human saphenous vein segments were characterized by marked deposition of HA in association with SMC. Interestingly, in contrast to native SVG, cyclooxygenase (COX)-2 expression by SMC and macrophages was detected only in arterialized SVG. In vitro in human venous SMC HAS isoforms were found to be differentially regulated. HAS2, HAS1, and HA synthesis were strongly induced by vasodilatory prostaglandins via G_s-coupled prostaglandin receptors. In addition, thrombin induced HAS2 via activation of PAR1 and interleukin 1ß was the only factor that induced HAS3. By small interfering RNA against HAS2, it was shown that HAS2 mediated HA synthesis is critically involved in cell cycle progression through G₁/S phase and SMC proliferation. In conclusion, the present study shows that HA-rich extracellular matrix is maintained after arterialization of vein grafts and might contribute to graft failure because of its proproliferative function in venous SMC. Furthermore, COX-2–dependent prostaglandins may play a key role in the regulation of HA synthesis in arterialized vein grafts.

Key Words: hyaluronic acid • extracellular matrix • cyclooxygenase-2 • vein graft stenosis

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