Cardiomyocytes with a reduced eNOS activity are able to produce elevated amounts of cytokines (TGFbeta and TNFalpha). Beside this autocrine TGFbeta effect, fibroblasts of a pressure overloaded heart produce TGFbeta, that is able to act as a paracrine stimulus. This study wants to distinguish between the parcrine and the autocrine stimulus in vivo. eNOS-deficient mice (eNOS-/- > eNOS+/­) and their non-transgenic littermates (eNOS+/+) were tested with regard to TGFbeta expression and other pro hypertrophic factors. In order to test the additional paracrine effect of TGFbeta such mice were crossed with TGFbeta over- expressing mice (TGFbeta-TG). These mice have a constitutive, hepatic release of active TGFbeta in their blood system. In eNOS knock-out mice the TGFbeta expression in the heart is increased in dependency of the grad of their eNOS deficiency (eNOS-/- > eNOS +/­). There were no survivable descendant born after crossing the TGFbeta-TG mice with the eNOS-/- mice. Crossing eNOS+/­ mice with TGFbeta-TG mice generated some survivable descendants. These animals had a higher systolic blood pressure and a reduced ventricular eNOS expression. The expression of eNOS in the aorta was totally down-regulated. Increased levels of cardiac produced TGFbeta results in the increased expression of genes associated with hypertrophy whereas extra-cardiac produced TGFbeta decreased eNOS expression resulting in hypertension and increased mortality.