Molecular mechanisms for local regulation of vascular tonics

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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.