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12: Effect of a short-course of recombinant human vascular endothelial growth factor on vascular dysfunction in a mouse model of preeclampsia induced by sFlt-1 over-expression

      Objective

      Inhibition of angiogenesis, endothelial dysfunction and nitric oxide deficiency have been implicated in the pathogenesis of preeclampsia. Over-expression of sFlt-1 in pregnant rodents induces a preeclampsia-like condition characterized by abnormal vascular function. Our objective was to test the hypothesis that vascular endothelial growth factor (VEGF121; an angiogenic factor and ligand for Flt-1) reverses the vascular dysfunction in pregnant mice over-expressing sFlt-1.

      Study Design

      CD-1 mice at day 8 of gestation were injected with adenovirus carrying sFlt-1 (109 PFU). At day 10 of gestation, the animals were randomly allocated to injections of VEGF121 (200μg/kg) or saline 100μl SC daily for 5 days (n=4/group). At day 18 of gestation, the mice were sacrificed and 2 mm segments of carotid artery were mounted in a wire myograph for isometric tension recording. Contractile response to KCl (10-5 M) and concentration-response curves to the endothelium-dependent vasodilator acetylcholine (Ach, 10-10-10-5 M), the endothelium-independent vasodilator sodium nitroprusside (SNP, 10-10-10-5 M), phenylephrine (PE, 10-10-10-5 M), and thromboxane A2 (TxA2, 10-10-10-6 M) were obtained. ANOVA was used for statistical analysis (significance: p<0.05).

      Results

      Responses to KCl were not significantly different between the VEGF and saline groups. The maximal response to PE in the VEGF group was significantly higher compared with the saline group (150.2±33.5 and 76.40±42.4). This difference was abolished in the presence of the nitric oxide synthase inhibitor L-NAME. There was an increase in the relaxant response to Ach in the saline group compared with the VEGF group. The response to SNP was higher, but not significantly, in the VEGF group. No differences were noted in the TXA2 responses.

      Conclusion

      A short course of VEGF does not reverse, and may actually worsen, the vascular dysfunction seen in this animal model of preeclampsia. The paradoxical response may be related to mechanisms induced by sFlt-1 that are independent of VEGF inhibition. Longer courses need to be evaluated.