Molecular Mechanisms for Mechanotransduction in Vascular Smooth Muscle and Endothelial cell

机械应变与表型变化有关，包括血管平滑肌细胞基因表达的改变；然而，导致核基因表达的机械转导的分子基础在很大程度上是未知的。通过FLEXERCELL^R菌株单元，我们发现血管平滑肌细胞的循环拉伸通过自分泌机制显著激活Jun n -末端激酶(JNK)/应激激活蛋白激酶（SAPK）。拉伸引起介质中ATP浓度随时间和强度的升高。拉伸诱导的JNK/SAPK的激活可以通过在培养基中加入清除ATP的己糖激酶或酰基酶而减弱。P_2受体拮抗剂和A_1亚型选择性P_1受体拮抗剂均能部分抑制拉伸诱导的JNK/SAPK活化。拉伸细胞的条件培养基含有刺激JNK/SAPK的活性。通过添加apyrase或P_1和P_2受体拮抗剂，使拉伸细胞在条件培养基中的jnk刺激活性减弱。外源性ATP或腺苷的加入诱导JNK/SAPK的剂量依赖性激活。这些结果表明，拉伸激活血管平滑肌细胞中的JNK/SAPK的机制涉及ATP及其水解产物腺苷对嘌呤受体的自分泌刺激。

Mechanical strain has been implicated in phenotypic changes, including alteration of gene expression in vascular smooth muscle cells ; however, the molecular basis for mechanotransduction leading to nuclear gene expression is largely unknown. By using a FLEXERCELL^R strain unit, we found that cyclic stretching of vascular smooth muscle cells dramatically activates Jun N-terminal kinase(JNK)/stress-activated protein kinase(SAPK)through an autocrine mechanism. Stretch causes time-and strength-dependent rise of the ATP concentration in media. The stretch-induced activation of JNK/SAPK is attenuated by the addition of hexokinase or apyrase that scavenge ATP in media. Both the P_2 receptor antagonist and the A_1 subtype-selective P_1 receptor antagonist partially inhibit stretch-induced activation of JNK/SAPK.The conditioned medium from stretched cells contains an activity to stimulate JNK/SAPK.The JNK-stimulating activity in the conditioned medium from stretched cells is attenuated by the addition of apyrase or P_1 and P_2 receptor antagonists. The addition of exogenous ATP or adenosine induces dose-dependent activation of JNK/SAPK.These results indicate that stretch activates JNK/SAPK in vascular smooth muscle cells through mechanisms involving autocrine stimulation of purinoceptors by ATP and its hydrolyzed product adenosine.