The Significance Of VSMC Apoptosis And Related Regulation In The Development And Rupture Of The Intracranial Aneurysm

Objective: To investigate the significance of VSMC apoptosis as well as itsregulation in the development and rupture of the intracranial aneurysm,meanwhile, the regulation mechanism of VSMC apoptosis were furtherelucidated by the establishment of cerebral aneurysm in rat and culturedVSMC.Methods: Pathological changes of cerebral aneurysms in both human andrat were was observed with transmission electron microscope; theimmunoreactivity of pJNK in both human and rat were measured byimmunohistochemical method; the gene expression levels of caspase-3 inhuman specimen were determined by using a real-time RT-PCR; theapoptosis of cultured VSMC exposed to shear stress was detected by TUNELmethod.Result: Transmission electron microscope show that chromatin condensation,cell shrinkage and cytoplasmic condensation as well as apoptotic bodyappearance of VSMCs in the human and rat aneurysmai tissue.Medial VSMCdensity in human cerebral aneurysm was noticeably reduced compared with the normal arteries (43.9 ± 4.3 VSMCs/HPF versus 222.8 ± 12.1 VSMCs/HPF, /KO.Ol), meanwhile the immunoreactivity scores of p-JNK of human was higher than that of the normal control (1.87 ± 1.06 versus 0.25 + 0.46, p < 0.01), the elevated pJNK expression was observed in aneurysmal tissue of rat (1.54 + 0.98 versus 0.17 + 0.24, p < 0.01). The ACt of the Caspase-3 gene expression in the cerebral aneurysm and abdominal aortic aneurysm were 2.67+1.22and 3.08+1.28 respectively, theAQ of control group is 5.83 +1.69( /><0.01 respectively), their expression were significantly upregulated in aneurysms compared with that of the normal artery(8.94-fold and 6.73-fold increase respectively). Significant difference in apoptosis were observed when VSMC culture in vitro exposed to shear stress(1.041,4.767 and 10.389dyne/cm2 respectively) afterl2h, the percentage of VSMC apoptosis were higher than those of the control group( 1.56+ 0.28 versus 0. 61 + 0.12, 1.95 + 0.23 versus 0. 55±0. 16 and 2.62±0.49 versus 0. 64± 0. 24, respectively,^ 0.01 ), further increase VSMC apoptosis occurred with the time-dependent shear stress, the values of the percentage of VSMC apoptosis were 2.76 + 0^ 2.75 + 0.68 and 3.60 + 0.68. Conclusion: 1: Excessive VSMCs exhibiting morphological apoptotic changes and siginificantly decreased medial VSMC density were observed in the intracranial aneurysm, these results strongly suggest that exorbitant VSMC apoptosis is involved in the pathogenesis of formation and rupture in the cerebral aneurysm. 2: According to the pathological alteration and clinical characterisitics, the cerebral aneurysm rupture falls into category of the leakage rupture and the burst rupture, the leakage rupture of intracranialaneurysm is intensively related to the abundant apoptosis of VSMC. 3: Elevated pJNK expression was occurred in human and animal aneurysm specimen, activated pJNK signal transduction pathway was associated with VSMC apoptosis, it would probably become the target for treatment the cerebral aneurysm by inhibition the apoptosis of VSMC caused by augmented JNK expression. 4: The upregulation of gene expression levels of caspase-3 which acted as downstream molecular of pJNK signal transduction pathway is probably implicated in the apoptosis of VSMC, the initiation of VSMC apoptosis may be induced by regional high shear stress.