CELL-CELL SIGNALING BETWEEN ADULT-RAT VENTRICULAR MYOCYTES AND CARDIAC MICROVASCULAR ENDOTHELIAL-CELLS IN HETEROTYPIC PRIMARY CULTURE

It is unclear whether signaling between endothelial cells and muscle cells within ventricular myocardium, known to be important during cardiac development, remains physiologically relevant in the adult heart. Also, the mechanisms regulating the synthesis and activation of locally acting autacoids such as endothelins, cytokines known to have potent effects on contractile function and gene expression in cardiac myocytes, are unknown, as are their cells of origin within ventricular muscle. Microvascular endothelial cells isolated from ventricular tissue of adult rats do not express endothelins constitutively. However, the appearance of preproendothelin MRNA can be increased in cardiac microvascular endothelial cells by heterotypic primary culture with adult rat ventricular myocytes. Cell-cell contact, or at least close apposition, appears to be necessary to increase preproendothelin mRNA, as medium conditioned by ventricular myocytes alone was ineffective when applied to monocultures of microvascular endothelial cells. The level of TGFbeta precursor mRNA is also markedly increased in microvascular endothelial cells in coculture and precedes the appearance of endothelin precursor transcripts. In coculture, TGFbeta acts as an autocrine cytokine, increasing endothelin precursor mRNA and inhibiting the rate of microvascular endothelial cell proliferation. This regulation of endothelial cell phenotype in heterotypic primary cultures suggests that dynamic, reciprocal cell-cell signaling may also be occurring between microvascular endothelium and ventricular myocytes in vivo.