Peripheral vascular disease: preclinical models and emerging therapeutic targeting of the vascular endothelial growth factor ligand-receptor system

Research output: Contribution to journalReview articlepeer-review

Abstract

Introduction: Vascular endothelial growth factor (VEGF)-A is a sought therapeutic target for PAD treatment because of its potent role in angiogenesis. However, no therapeutic benefit was achieved in VEGF-A clinical trials, suggesting that our understanding of VEGF-A biology and ischemic angiogenic processes needs development. Alternate splicing in VEGF-A produces pro- and anti-angiogenic VEGF-A isoforms; the only difference being a 6-amino acid switch in the C-terminus of the final 8th exon of the gene. This finding has changed our understanding of VEGF-A biology and may explain the lack of benefit in VEGF-A clinical trials. It presents new therapeutic opportunities for peripheral arterial disease (PAD) treatment. Areas covered: Literature search was conducted to include: 1) predicted mechanism by which the anti-angiogenic VEGF-A isoform would inhibit angiogenesis, 2) unexpected mechanism of action, and 3) how this mechanism revealed novel signaling pathways that may enhance future therapeutics in PAD. Expert opinion: Inhibiting a specific anti-angiogenic VEGF-A isoform in ischemic muscle promotes perfusion recovery in preclinical PAD. Additional efforts focused on the production of these isoforms, and the pathways altered by modulating different VEGF receptor-ligand interactions, and how this new data may allow bedside progress offers new approaches to PAD are discussed.I.

Original languageEnglish (US)
Pages (from-to)381-391
Number of pages11
JournalExpert Opinion on Therapeutic Targets
Volume25
Issue number5
DOIs
StatePublished - 2021

Keywords

  • Endothelium
  • alternate splicing
  • angiogenesis
  • atherosclerotic occlusion
  • chronic limb ischemia
  • chronic limb-threatening ischemia
  • ischemia
  • macrophage polarization
  • peripheral artery disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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