Myocyte-Endothelial Cell Cross Talk Involves p38 MAP Kinase Mediated Paracrine Signaling from Cardiomyocytes

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During periods of stress, the heart undergoes a number of physiological and molecular changes. These changes occur through the activation or inhibition of various signaling pathways and take place not only in cardiac myocytes but also the surrounding cells such as endothelial cells, fibroblasts, and inflammatory cells. Communication between these various cells types allows for changes on the cellular level to be translated to changes at the organ level. Previous studies have shown the need for balance between myocyte demand and vascular supply. Inadequate vasculature during periods of increased work load has been shown to lead to functional changes in the myocardium. The exact nature of how this balance is achieved has yet to be elucidated. p38 MAP kinase, a stress activated kinase, is a well studied signaling pathway associated with cardiac function. While its specific role is still somewhat controversial, it has been implicated in myocyte apoptosis, hypertrophy, proliferation and contractility. While previous studies have focused only on myocytes, it remains to be determined what role p38 plays in cell-cell communication. To address this issue, we have investigated the role p38 signaling plays in myocyte-endothelial cell cross talk. Using myocyte specific p38 knockout animals, we have demonstrated that in response to pressure overload, the KO animals showed a significant decrease in vascular marker expression compared to their WT littermates as assessed by quantitative real-time PCR and immunohistochemial analyses. This attenuated vascular induction was also accompanied by a greater loss of function in the KO animals. To better understand this, we have begun to study this myocyte-endothelial communication in vitro. Using conditioned media from neonatal rat ventricular myocytes applied to endothelial cells in a 3D gel culture, we have shown that over activation of p38 in myocytes leads to increased cell growth in cultured endothelial cells. This is accompanied by a significant increase in VEGF mRNA levels in the myocytes with p38 over activation. This indicates that p38 plays a role in myocyte-endothelial cell communication. Therefore, we hypothesize that p38 signaling in myocytes is contributing to cross-talk with the endothelial cells via secreted paracrine factors and that disruption in the myocyte stress response signaling mediated by p38 can lead to detrimental vascular deficiency in stressed myocardium.