Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia

Abstract

Preeclampsia is characterized by the development of elevated blood pressure during the second and third trimesters of pregnancy that is accompanied by end organ dysfunction. The pathogenesis of preeclampsia is multifactorial but is commonly characterized by endothelial dysfunction and the overproduction of antiangiogenic factors, including the soluble VEGF (vascular endothelial growth factor) receptor sFlt-1 (soluble Fms-like tyrosine kinase receptor 1). Previously, administration of exogenous VEGF-A, bound to a carrier protein called ELP (elastin-like polypeptide), significantly reduced free sFlt-1 levels and attenuated the hypertensive response in a rodent model of preeclampsia. However, VEGF-A administration induces multifactorial effects mediated through its direct activation of the Flk-1 receptor. In response to this, we developed a therapeutic chimera using ELP bound to VEGF-B, a VEGF isoform that binds to sFlt-1 but not to Flk-1. The purpose of this study was to evaluate the in vitro activity and pharmacological properties of ELP-VEGF-B and to test its efficacy in the reduced uterine perfusion pressure rat model of placental ischemia. ELP-VEGF-B was less potent than ELP-VEGF-A in stimulation of endothelial cell proliferation and matrix invasion, indicating that it is a weaker angiogenic driver. However, after repeated subcutaneous administration in pregnant rats, ELP-VEGF-B was maternally sequestered and reduced blood pressure when compared with saline treated animals following induction of placental ischemia (123.38±11.4 versus 139.98±10.56 mm Hg, P =0.0129). Blood pressure reduction was associated with a restoration of the angiogenic capacity of plasma from rats treated with ELP-VEGF-B. ELP-VEGF-B is a nonangiogenic, maternally sequestered protein with potential efficacy for treatment of preeclampsia.

New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations

“…Similar results were obtained for the chimera ELP with VEGF isoform type B; however, this therapeutic peptide seemed to be a weaker proangiogenic driver than ELP-VEGF-A. It demonstrates lower stimulation of endothelial cell proliferation and matrix invasion than complex carriers isoform A, as indicated by in vitro studies [154]. Interestingly, these therapeutic peptides are safe for foetuses; the data indicates that ELP is a drug carrier sequestered in the maternal system and although it might localise in the placenta, it is not detected in the circulation of foetuses [153,156].…”

“…Elastin-like polypeptide (ELP) is a nonimmunogenic, engineered particle composed of a repeating five amino acid motif; it is used as a carrier to stabilise therapeutic peptides and to protect them against degradation and removal from the organism [151,152]. The administration of a chimera of ELP linked with the vascular endothelial growth factor isoform type A (VEGF-A) or isoform type B (VEGF-B) to rats with PE induced by surgery, relays on the reduction of uterine perfusion pressure, was found to significantly block averse pregnancy [153,154]. VEGF-B is a structural homologue of VEGF-A, and both bind to the VEFGR1 receptors, including their soluble version, i.e., sFlt1 [155].…”

Application of Elastin-like Polypeptide in Tumor Therapy

“…Despite the significant advantages and success achieved by introducing PEG and HSA in target proteins, a highly efficient, cost-effective and reliable precision genetically designed protein-polymer fusion complex with high yield, specificity, bioactivity and well sustained pharmacodynamics and pharmacokinetics is required. The emergence of ELPs as a classical binding module to facilitate the fusion and delivery of therapeutic molecules or provide a surface site for the attachment and display of PDs to increase pharmacokinetic properties has become the subject of intense research focus [ 50 , 51 ]. Thus, by using ELPs as a delivery module, target molecular drugs or peptide drugs can be encapsulated, attached or displayed on the surface of ELP nanoparticles.…”

First‐trimester plasma extracellular heat shock proteins levels and risk of preeclampsia

“…14 During the second stage of this abnormal placentation, there is a proangiogenic and antiangiogenic imbalance, 15,16 including soluble Fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). [17][18][19][20] The decrease in these proteins in plasma is correlated with the severity of PE and with the development of adverse pregnancy outcomes [21][22][23] attributed to an increase in pro-inflammatory cytokines. 24,25 These serum markers and their indices (sFlt-1/PIGF ratio) are only used in prediction models later on in pregnancy.…”