Study in Signal Transduction of Platelet-derived Growth Factor which Participates in Chronic Hypertension

在培养的自发性高血压大鼠(SHR)的血管平滑肌细胞(VSMC)中，除了表达β受体(PDGFR-β)外，还表达了血小板衍生生长因子(PDGF)α受体(PDGFR-α)和β受体(PDGFR-β)。在SHR细胞中，能与PDGFR-α结合但不能与PDGFR-β结合的PDGF-AA刺激蛋白质合成而不激活DNA合成，而能与这两种受体结合的PDGF-BB则引起DNA合成的激活。由于VSMC体积增大导致的血管壁增厚在慢性高血压中普遍存在，PDGFR-α在VSMC中的异常表达被认为是导致高血压时血管肥厚的重要病理生理因素。PDGF-AA和-BB刺激表达PDGFR-α的其他类型细胞的DNA合成。因此，PDGF-AA诱导的SHR来源的VSMC的细胞反应是非常异常的。为了阐明PDGF-AA不能刺激SHR细胞DNA合成的原因，我通过与PDGF-BB的比较，研究了PDGF-AA在这类细胞中的信号机制。PDGF-BB激活磷脂酶D和二酰甘醇激酶导致磷脂酸(PA)的形成，但在PDGF-AA诱导的细胞中不产生PA。PA的形成被认为是激活VSMC DNA合成的重要因素。血管紧张素II和转化生长因子β(TGF-β)降低了SHR来源的VSMC中PDGFR-α的表达水平，而白介素1-β(IL-1β)上调了受体水平。然而，即使WKY来源的VSMC与IL-β或抗转化生长因子-β共同孵育，PDGFR-α也没有出现。

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.