Introduction: 

Two independent studies show that 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 understand certain mechanisms of blood pressure regulation. Our strategy was to study in a first instance, whether smooth muscle reactivity in different vascular beds was different due to the genetic manipulation and we tested further whether FGF-2 had vasoactive properties by itself.

Methods and results: 

Vessel segments from a. saphena, mesenterica and gracilis were dissected from FGF-2 KO mice or heterozygote littermates (n=4 ea) and investigated either under isometric (a. mesenterica, a. saphena, a. gracilis) or under isobaric conditions (a. gracilis). Methoxamine was used as vasoconstrictor and acetycholine (Ach) as relaxant in isometric setups. In all setups, no differences in the smooth muscle cell vasoactivity were found comparing animals bearing FGF-2 or lacking it. The same was true in case of myogenic response (pressure steps: 40, 80, and 120 mmHg). In combination with data from the literature, demonstrating that in both types of mice the minute-volume of the hearts are 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 and the reason for the lower pressure systemically might be a consequence of the lack of FGF-2. Therefore, we investigated a possible modulator role of FGF-2 in acetylcholine (Ach) induced vessel dilatation. Similar as above, the same vessel types (from wild type animals) were exposed to Ach with and without a combination of FGF-2 (20ng/ml). Vessel which were treated with Ach in combination with FGF-2 showed significant less dilation than those of control settings with Ach only. These findings indicate that FGF-2 might inhibit endothelial nitric oxide (NO) production. To prove this hypothesis, freshly prepared aortic segments were stimulated with Ach and the resulting NO production was quantified by NO₂ measurements. Indeed, Ach induced a significant NO production, which was completely abolished by simultaneous incubation with FGF-2. Furthermore, in FGF-2 KO animals we found a significant higher NO_x level supporting the fact that FGF-2 might antagonize a NO production. FGF-2 application alone had no effects on vessel diameter. In earlier studies, we showed that shear stress caused by elevated flow leads to the active release of FGF-2 from EC. In addition shear stress represents a potent stimulus for NO mediated vessel dilatation. Thus the findings so far were verified in cell culture exposing porcine endothelial cells to elevated laminar flow. As expected EC which were subjected to shear stress (16dyn/cm²) showed a transient nitric oxide (NO) production (3,6 fold, n=6). However, inhibition of FGF-2 by blockade of its receptor shifted those characteristic transient NO production to a now steadily increasing one, leading to a significant higher accumulation of NO₂ in the supernatant media (8 fold, n=6). Similar results were found if the release of FGF-2 from flow exposed EC were inhibited.

Conclusion: 

In summary, the data of this study indicate that besides to its growth factor 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, where the NO production has to be turned off quickly after its induction; otherwise, the resulting drop in blood pressure caused by an inadequate dilation would be deleterious.