Differential Regulation of Hyaluronic Acid Synthase Isoforms in Human Saphenous Vein Smooth Muscle Cells: Possible Implications for Vein Graft Stenosis

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 p...

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Bibliographic Details
Published in:Circulation research 2006-01, Vol.98 (1), p.36-44
Main Authors: van den Boom, M, Sarbia, M, von Wnuck Lipinski, K, Mann, P, Meyer-Kirchrath, J, Rauch, B H, Grabitz, K, Levkau, B, Schrör, K, Fischer, J W
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Biological and medical sciences
Cells, Cultured
Cyclooxygenase 2 - analysis
Female
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Enzymologic
Glucuronosyltransferase - genetics
Glucuronosyltransferase - physiology
Graft Occlusion, Vascular - etiology
Humans
Hyaluronan Synthases
Hyaluronic Acid - analysis
Interleukin-1 - pharmacology
Isoenzymes - genetics
Male
Middle Aged
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - enzymology
Platelet-Derived Growth Factor - pharmacology
Proto-Oncogene Proteins c-sis
RNA, Small Interfering - pharmacology
Saphenous Vein - enzymology
Saphenous Vein - transplantation
Thrombin - pharmacology
Tunica Intima - pathology
Vertebrates: cardiovascular system
Citations: Items that this one cites
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Summary: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 Gs-coupled prostaglandin receptors. In addition, thrombin induced HAS2 via activation of PAR1 and interleukin 1β 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.
ISSN:0009-7330
1524-4571
DOI:10.1161/01.RES.0000199263.67107.c0