Role Of PDGF-AA And PDGFR-α In Proliferation And Hypertrophy Of Vascular Smooth Muscle Cells In SHRs

Backgroud:Smooth muscle cells is one of components in vascular wall,it is one of important agent to determinate the vascular reactivity and vascular modeling. Proliferation and hypertrophy of vascular smooth muscle cells (VSMC) and vascular remodeling have been considered to contribute to pathophysiological changes in step-up of vascular resistance in hypertention. Therefore, How to control vascular smooth muscle cells function is the key issue in prevention and treatment of hypertention. Platelet-derived growth factor (PDGF) is one of the major mitogens and is responsible for proliferation and migration of VSMC. The dimeric ligands (PDGF-AA,-AB,-BB) exert their biological effects by binding to PDGFR- a ,but only PDGF-AB,-BB to PDGFR- P . The signal transduction phenotype mediated by PDGFR is the key link in control of proliferation and hypertrophy of VSMC and vascular remodeling. [Ca2+]i and tyrosine kinase play an important role in signal transduction pathway. Thereforce, this study aim is trying to make somethings clear as follows: 1. The difference of expression of platelet derived growth factor-AA (PDGF-AA) and PDGFR- a in VSMC in spontaneously hypertension rats(SHR)/Wistar rats. 2. The effect of PDGF-AA on the proliferation and hypertrophy of VSMC in SHR/Wistar rats. 3. The effect of truncated PDGFR- a on proliferation and hypertrophy of VSMCs induced by PDGF-AA in SHRs. 4. The role of [Ca2+]i and tyrosine kinase in proliferation and hypertrophy of VSMCs induced by PDGF-AA in SHRs. Methods:1.The difference of expression of platelet derived growth factor-AA(PDGF-AA) and PDGFR- a in VSMC in spontaneously hypertension rats(SHR)/Wistar rats was observed by Western blot, RT-PCR.2.The effect of PDGF-AA on 3H-Leu/3H-TdR incorporation, cell cycle and expression of proliferating cell nuclear antigen(PCNA), transcription regulator (c-myb/c-myc) mRNA of VSMC in SHR/Wistar rats.3.The effect of truncated PDGFR- a on 3H-Leu/3H-TdR incorporation, cell cycle, cytosolic calcium and expression of PCNA, transcription regulator (c-myb/c-myc) mRNA, of VSMCs induced by PDGF-AA in SHRs.4. The role of tyrosine kinase inhibitor in 3H-Leu/3H-TdR incorporation, cell cycle cytosolic calcium and expression of PCNA, transcription regulator (c-myb/c-myc) mRNA of VSMCs induced by PDGF-AA in SHRs.5. The role of Ca2+ channel blocker in 3H-Leu/3H-TdR incorporation, cell cycle cytosolic calcium and expression of PCNA, of VSMCs induced by PDGF-AA in SHRs.Results:1. PDGF-AA and PDGFR- a expression was markedly increased in SHR-VSMC than that in Wistar-VSMC(P<0.01). Dose-dependent 3H-Leu /3H-TdR incorporation, cell cycle and expression of PCNA, transcription regulator (c-myb/c-myc) mRNA were observed in SHR-VSMC induced by PDGF-AA (PO.01), but not in Wistar-VSMC (P>0.05).2. 3H-Leu/3H-TdR incorporation, cell cycle, cytosolic calcium and expression of PCNA, transcription regulator (c-myb/c-myc) mRNA induced by PDGF-AA were significantly inhibited with truncated PDGFR- a (PO.01).3. Dose-dependent genistein inhibited 3H-Leu/3H-TdR incorporation, cell cycle cytosolic calcium and expression of PCNA, transcription regulator (c-myb/c-myc) mRNA induced by PDGF-AA were observed in SHR-VSMC (PO.01).4. Dose-dependent nimodipine inhibited 3H-Leu/3H-TdR incorporation, cellcycle cytosolic calcium and expression of PCNA, induced by PDGF-AA were observed in SHR-VSMC(P<0.01). Conclusion:1. Spontaneously expression increasing of PDGF-AA and PDGFR- a in spontaneously hypertension rats (SHRs) may be one of the important factors on vascular reactivity and vascular modeling mediated through proliferation and hypertrophy in SHR-VSMC.2. Truncated PDGFR- a significantly blocked the proliferation and hypertrophy of VSMC induced by PDGF-AA in SHRs.3. Tyrosine protein kinase and cytosolic calcium signal play an important role in proliferation and hypertrophy of VSMC induced by PDGF-AA in SHRs.