We report here that continuous infusion of VEGF121 in pregnant mice attenuated AT1-AA-induced hypertension and proteinuria, the hallmark features of PE. In addition, we demonstrate that infusion of VEGF121 blunted other features induced by PE-IgG in the pregnant mice including kidney damage, renal dysfunction featured with increased BUN and placental impairment coupled with decreased endothelial cell content. Overall, our findings reveal that VEGF121 infusion is a promising therapeutic possibility to attenuate autoantibody-induced features of PE.
VEGF is important in renal function where it is highly expressed by glomerular podocytes25
and targets VEGF receptors present on glomerular endothelial cells.26
Initial evidence for the potential importance of VEGF signaling in renal–vascular function came indirectly from clinical trials of anti-VEGF therapy for the treatment of certain cancers, where unexpected side effects included hypertension and proteinuria.27
Maynard et al
realized that excessive sFlt-1, because of its anti-VEGF properties, could account for the same features in PE and tested this possibility by introducing recombinant adenoviruses encoding sFlt-1 into rats. Their results showed that sFlt-1 mediated a dose-dependent increase in hypertension, proteinuria and characteristic renal findings termed glomerular endotheliosis when overexpressed in pregnant or nonpregnant rats. Clinical studies have shown that the increase in sFlt-1 in pregnant women precedes the onset of symptoms of PE by several weeks28
and that the levels of circulating sFlt-1 achieved are proportional to disease severity. Other studies have shown that infusion of sFlt-1 via controlled release by osmotic minipumps resulted in hypertension and proteinuria in pregnant rats.29
In a rat model of PE based on experimentally-induced placental ischemia, excessive sFlt-1 production has also been implicated in hypertension and proteinuria.30
We have previously shown that increased sFlt-1 is also associated with the autoantibody-injection model of PE in pregnant mice. It is likely that the beneficial effects of VEGF in these animal models of PE results from neutralizing the antiangiogenic effects of excessive sFlt-1. Thus, the evidence implicating sFlt-1 in the pathogenesis of PE is considerable and compelling and the use of VEGF therapy to neutralize the effects of excessive sFlt-1 is especially attractive.
The placental ischemia model of PE in rats (reduced uteroplacental perfusion pressure (RUPP)) and the autoantibody-injection model in pregnant mice share a number of important features including elevated sFlt-1, tumor necrosis factor-α, interleukin-6, and AT -AA.30–33
1 Additional evidence shows that all of these molecules can induce hypertension and proteinuria when introduced into pregnant animals.5,11,16,31–35
It has also been shown that antagonism of each of these molecules significantly reduces hypertension and proteinuria, indicating that each contributes to disease pathology. Recent evidence supports a role for endothelin-1 as a mediator of sFlt-1-induced hypertension.36
In the latter studies infusion of sFlt-1 resulted in increased production of preproendothelin-1 mRNA in the kidney cortex and hypertension that was prevented by antagonism of the endothelin A receptor, the target of endothelin-1. Thus the hypertensive and proteinuric effects of sFlt-1 are observed in pregnant and nonpregnant animals and are mediated by endothelin-1 signaling pathways. The antihypertensive effects of VEGF therapy may be mediated by stimulating endothelial cells to produce nitric oxide and vasodilatory prostacyclins, resulting in vascular smooth muscle relaxation.37
Because VEGF stimulates the production of vasodilatory substances such as nitric oxide and prostacyclins it is also possible that VEGF121
therapy can function as a general antihypertensive agent to counteract the hypertensive effects of a number of molecules in addition to sFlt-1.
The major focus of the research reported in this study was to evaluate the therapeutic potential of VEGF121
in our autoantibody-injection model of PE in mice. For this reason we examined the potential therapeutic effect of VEGF121
with regard to the defining clinical features of the disease including hypertension, proteinuria, renal abnormalities, and endothelial damage. We have shown here that VEGF121
infusion prevents these autoantibody-induced features of PE. In view of the data presented here showing that VEGF infusion reduced autoantibody-induced placental damage and improves placental endothelial cell content it will be of interest to examine the effects of VEGF121
therapy on fetal and placental weights and development. This issue has been addressed in two experimental models of PE in rat, an adenovirus-induced sFlt-1 over expression model and the RUPP model. No reduction in placental and fetal size was reported for the sFlt-1 over expression model and no effect of VEGF treatment was observed.17
The RUPP model is characterized by reduced fetal weight and no reduction in placental size. The therapeutic dose of VEGF121
did not result in a change in either of these parameters.20
Thus, in the RUPP model of PE the reduction in fetal weight was not corrected by the dose of VEGF121
therapy that was most effective in preventing the maternal features of PE. We have recently reported that the introduction of AT1
-AA into pregnant mice resulted in smaller placentas and fetuses.23
It will be interesting to examine the effects of VEGF121
therapy on placental and fetal weights and development in the autoantibody-injection model of PE in pregnant mice.
In conclusion, we provide for the first time in vivo
evidence that infusion of VEGF121
significantly attenuates key features of PE induced by AT1
-AA in pregnant mice. In addition to the antibody-injection model of PE presented here, the therapeutic benefit of VEGF121
infusion has also been demonstrated in two other animal models of PE. The first was a rat model of PE generated by adenoviral over expression of sFlt-1. In this model, VEGF121
therapy attenuates hypertension and prevents kidney damage.17
More recently the benefit of VEGF121
therapy was shown in an animal model of PE based on experimentally-induced RUPP20
Both of these models, as with the antibody-injection model used in the present report, are characterized by excessive production of sFlt-1. However, the RUPP model and the antibody-injection model are also characterized by increased production of other molecules that have been associated with PE, including tumor necrosis factor-α, interleukin-6, and sEng. Our findings are in agreement with those from the RUPP model and show that VEGF121
prevents hypertension and renal dysfunction in the presence of increased levels of multiple other factors associated with PE. Thus, the potential benefit of VEGF therapy has now been shown in three preclinical models of PE justifying serious consideration of this as a therapeutic approach for use in women with PE.