| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Vascular stenosis occurs in many patients after angioplasty because of neointima formation due to migration and proliferation of vascular smooth muscle cells (SMC). A variety of growth factors have been implicated in neointima formation including platelet-derived growth factor (PDGF) and angiotensin II. In this study, we obtained several new findings. First, we demonstrated the important role of PDGF in the phase of neointimal development after arterial injury. We administered Trapidil, which is thought to be the only drug blocking the action of PDGF almost selectively, during the phase of developing the neointima formation in a rat carotid balloon injured model. Second, we demonstrated endogenous PDGF-B chain among PDGFs played the most imporlant role during the same phase in a rat model. We made the soluble extracellular region of PDGF-β receptor (PDGFXR) as a selective antagonist ofPDGF-B. In cultured SMC, we found PDGFXR abolishes function of PDGF-B i.e. stimulation of PDGF-β receptor tyrosine phosphoroyation and DNA synthesis. In a rat carotid balloon injured model, we demonstrated that PDGF-β receptor is activated more significantly in the phase of the neointima development. Transfection of injured rat carotid arteries with adenoviral vector containing PDGFXR gene nearly completely suppressed activation of PDGF-α receptor and reduced neointima formation. Third, we found that neointimal SMC produced PDGF-B chain in response to angiotensin II (Ang II). Fourth, we demonstrated Ang II activated several molecules, which act as a switch of signal transduction. PDGF-B production via Ras, ERK, JNK, and Egr-1. These results indicate that PDGF-B chain, produced locally by neointimal SMC, plays an essential role in neointima formation after arterial injury. They also suggest the utility of PDGFXR as a therapeutic gene for preventing vascular stenosis after arterial injury.
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