|Budget Amount *help
¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1995 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1994 : ¥1,100,000 (Direct Cost : ¥1,100,000)
In cultured vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR), in contrast to cells from normotensive rats (Wister-Kyoto rats ; WKY), the platelet-derived growth factor (PDGF) alpha receptor (PDGFR-alpha), in addition to the beta receptor (PDGFR-beta), is expressed. In the SHR cells, PDGF-AA,which can bind PDGFR-alpha but not PDGFR-beta, stimulated protein synthesis without activation of DNA synthesis, whereas PDGF-BB,which can band the both types of receptors, caused the activation of DNA synthesis. Since thickening of the vascular wall due to an increase in the size of VSMC is commonly involved in chronic hypertension, abnormal expression of PDGFR-alpha in VSMC is thought to be pathophysiologically important factor which may induce vascular hypertrophy during hypertension.
PDGF-AA as well as -BB stimulates DNA synthesis in other types of cells in which PDGFR-alpha is expressed. Thus, cell response observed in SHR-derived VSMC elicited by PDGF-AA is quite abnormal. To clarify why PDGF-AA does not stimulate DNA synthesis in the SHR cells, I examined signaling mechanism of PDGF-AA in this cell type by comparison with that of PDGF-BB.PDGF-BB activated phospholipase D and diacylglyerol kinase resulting in the formation of phosphatidic acid (PA) ; however, PA formation did not occur in cells elicited by PDGF-AA.PA formation has been reported to be important to activate DNA synthesis in VSMC.
Angiotensin II and transforming growth factor beta (TGF-beta) decreased the expression level of PDGFR-alpha in SHR-derived VSMC,whereas interleukin 1-beta (IL-1beta) up-regulated the receptor level. However, PDGFR-alpha did not appear even if WKY-derived VSMC was incubated with IL-beta or anti-TGF-beta.