O213	Regulation and function of hyaluronic acid synthases (has) in human saphenous vein smooth muscle cells.
1M.Van den Boom, 2M.Sarbia, 1P.Mann, 1J.Meyer-Kirchrath, 1B.Rauch, 3K.Grabitz, 1K.Schrör, 1J.W.Fischer
1Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, DE; 2Institut für Allgemeine Pathologie der Technischen Universität, München, DE; 3Klinik für Gefäßchirurgie und Nierentransplantation, Universitätsklinikum Düsseldorf, Düsseldorf, DE.

Autologous saphenous vein bypass grafts (SVG) are frequently compromised by neointimal thickening and subsequent atherosclerosis leading to graft failure. Hyaluronic acid (HA) is thought to augment the progression of atherosclerosis. The aim of the present study was (i) to investigate HA accumulation in native and explanted arterialized SVG, (ii) to identify factors that regulate HA-synthase (HAS) expression and HA-synthesis and (iii) to study the function of the HAS2-isoform. In native SVG expression of all three HA-synthase (HAS)-isoforms was detected by RT-PCR. Furthermore native and arterialized human saphenous veins segments were generally characterized by marked deposition of HA in association with SMC as shown by immunohistochemistry. Interestingly, in contrast to native SVG cyclooxygenase-2 (COX-2) expression by SMC and macrophages was detected only in the arterialized SVG. In vitro HAS-isoforms were found to be differentially regulated in human venous SMC. HAS2, HAS1 and HA-synthesis were strongly induced by vasodilatory prostaglandins (PG) via Gs-coupled PG-receptors. In addition, thrombin induced HAS2 via activation of PAR1 and interleukin-1ß was the only factor that induced HAS3. By small interfering RNA it was shown that HAS2 mediated HA-synthesis is critically involved in DNA-synthesis and SMC-proliferation. In conclusion, the present study shows that HA-rich ECM is maintained after arterialization of vein grafts and that HA might contribute to graft failure due to its pro-proliferative function in venous SMC. Furthermore, the data suggest a key role of COX-2 dependent prostaglandin-synthesis in regulation of HA-synthesis in arterialized vein grafts.

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