Introduction: 

Mice lacking the growth factor FGF-2 are suffering from reduced systemic blood pressure (-10 mmHg vs wt). We hypothesized that knowledge about the process of this chronic low blood pressure would help to develop strategies to treat hypertension. Vessel segments from a. saphena, mesenterica and gracilis were dissected from FGF-2 KO mice or heterozygote littermates (n=4) and investigated in isometric setups using methoxamine as vasoconstrictor and acetycholine as relaxant. In all setups, no differences in the smooth muscle cell vasoactivity were found between animals bearing FGF-2 or lacking it. In combination with data from the literature demonstrating that in both types of mice the heart-minute-volumes were unchanged, these findings indicate that the reduced blood pressure in mice without FGF-2 expression could not be due to a smooth muscle cell phenotype per se. Therefore the reason for lower systemically blood pressure might be solely a consequence of the lack of FGF-2.

Methods and results: 

Porcine endothelial cells (EC) subjected to laminar flow (16dyn/cm²) showed only a transient nitric oxide (NO) production (3,6 fold, n=6). In earlier studies, we showed that fluid flow leads to the release of FGF-2 from EC. Therefore, we inhibited a possible FGF-2 action by blockade of its receptor and found that the characteristic transient NO production was now steadily increasing leading to a higher accumulation of NO in the supernatant media (8 fold, n=6). Similar results were found if the release of FGF-2 from flow exposed EC were inhibited per se. These findings indicate that FGF-2 might inhibit or antagonize the nitric oxide synthase (eNOS) in EC. To prove this, eNOS in cultured EC was stimulated with Histamine or VEGF to induce NO formation. Both stimuli of NO production could be inhibited by FGF-2. These inhibitory effects of FGF-2 were abolished either by blockade of the FGF-2 receptor or by wortmannin, indicating a specific FGF-2 effect which was PI3-kinase-signalling dependent. Since FGF-2 was able to turn down the NO production induced by different stimuli, we hypothesize that the virtual step of inhibition could be close to the eNOS enzyme itself and tested whether this was mediated by phosphatases. Indeed, first screening experiments showed that inhibition of phosphatases might reverse FGF-2 inhibitory effects. Finally, measurements in blood serum yielded, consistent with the results above, that mice lacking FGF-2 had significant more NO₂ in peripheral blood as control littermates.

Conclusion: 

In summary, the data of this study indicate that besides its angiogenic activity FGF-2 might play a significant role in the regulation of blood pressure by antagonizing the NO production. Especially in case of flow-induced dilatation, NO production should be turned off quickly after its induction; otherwise, the resulting drop in blood pressure caused by an inadequate dilation would be deleterious for the organ blood supply.