Molecular mechanisms for local regulation of vascular tonics

在本研究中，我们研究了血管张力局部调控的分子机制。甲状旁腺激素相关肽（PTHrP）是一种局部产生的血管松弛肽，以旁分泌或自分泌方式起作用。我们发现血管平滑肌拉伸导致PTHrP mRNA的增加。在研究细胞信号传导介导拉伸诱导的PTHrP基因表达时，我们发现血管平滑肌细胞拉伸激活Jun-N末端激酶（JNK），并在较小程度上激活MAP激酶（MAPK）。在拉伸细胞的条件培养基中，检测到jnk刺激活性。我们发现ATP在条件培养基中具有刺激jnk的活性。我们的数据表明，血管平滑肌细胞在拉伸时释放的ATP作用于血管平滑肌上的G蛋白偶联P_2嘌呤受体，从而激活JNK和MAPK。目前已知的G蛋白偶联P_2嘌呤受体有7种亚型。我们发现在血管平滑肌细胞中至少有两种表达P_<2Y2> (=P_<2U>)和P_<2Y6>。发现这两种亚型都与MAPK和JNK级联相耦合。JNK被药理学激活后，PTHrP mRNA升高。这些结果表明，拉伸刺激JNK的机制涉及自分泌ATP激活P_2嘌呤受体，导致PTHrP基因表达。

In the present study we studied molecular mechanisms underlying local regulation of vascular tone. Parathyroid hormone-related peptide (PTHrP) is a locally produced vasorelaxant peptide, which acts in a paracrine or autocrine fashion. We found that exposure of vascular smooth muscle to stretch led to an increase in mRNA of PTHrP.While investigating cellular signalling to mediate stretch-induced PTHrP gene expression, we found that stretch of vascular smooth muscle cells activates Jun-N terminal kinase (JNK) and, to a lesser extent, MAP kinase (MAPK). In the conditioned medium of cells exposed to stretch, a JNK-stimulating activity was detected. We identified ATP as a JNK-stimulating activity in the conditioned medium. Our data suggest that ATP released from vascular smooth muscle cells upon stretching acts on G protein-coupled P_2 purinoceptors on vascular smooth muscle to active JNK and MAPK.There are seven subtypes of G protein-coupled P_2 purinoceptors so far known. We found that in vascular smooth muscle cells, at least two of them, P_<2Y2> (=P_<2U>) and P_<2Y6>, are expressed. Both subtypes are found to be coupled to MAPK and JNK cascades. When JNK is activated pharmacologically, PTHrP mRNA is increased. These results suggest that stretch stimulates JNK through a mechanism involving P_2 purinoceptor activation by autocrine ATP,leading to PTHrP gene expression.