Abstract 544: Development of a Stabilized Bioactive VEGF Chimera for the Management of Preeclampsia

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Abstract

Preeclampsia is a gestational hypertensive disorder which occurs in 5-10% of all pregnancies in the US. While the underlying cause of the disease is unknown, there is growing recognition that placental ischemia leads to the secretion of pathogenic factors into the maternal blood stream, perhaps most notably the VEGF antagonist sFlt-1. Circulating sFlt-1 sequesters free VEGF and decreases the overall level of VEGF available for cell signaling. Preclinical experiments suggested a palliative effect of VEGF delivery in preeclampsia models, but translation of this therapy is severely hampered by the short half-life of free VEGF and convenient routes of administration. We have recently constructed a VEGF chimera fused to an Elastin Like Polypeptide (ELP) polymer with significantly increased in vivo half-life and stability which appears to retain full VEGF signaling activity. Importantly, we have preliminary evidence that the ELP fusion prevents placental translocation and fetal exposure, preventing harmful fetal effects. ELP-VEGF stimulated normalized HUVEC proliferation at 72hr was dose dependent from 1-100nM, and was equivalent to that of free VEGF (2 ± 0.25 for ELP-VEGF vs 1.94 ± 0.18 at 100nM, p<0.05 versus control for both). Free VEGF (20nM) induced tube formation by HUVECs (8.8 ± 2 vs 14.5 ± 3 tubes/field, p<0.05). Likewise ELP-VEGF significantly increased tube formation compared to control cells (p<0.05), and trended toward augmentation of tube formation versus VEGF alone (18.6 ±4 tubes per frame, p=0.07), though this did not reach significance. Finally, ELP-VEGF (50nM) stimulated HUVEC migration through matrigel (9.9 ± 0.7 vs 3.4 ± 0.3 cells/field, p<0.05) to a similar extent to free VEGF (8.4 ± 0.6 cells/field, p<0.05 vs control). Together, these data suggest that ELP-VEGF retains full VEGF signaling potential, which along with enhanced pharmacokinetic parameters could be a useful therapeutic for the restoration of VEGF signaling in the preeclamptic patient.

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