Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 25, Issue 5, Pages 381-391Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14728222.2021.1940139
Keywords
Endothelium; macrophage polarization; alternate splicing; angiogenesis; ischemia; peripheral artery disease; chronic limb-threatening ischemia; atherosclerotic occlusion; chronic limb ischemia
Categories
Funding
- [R01HL141325]
- [R01HL148590]
- [RO1HL150003]
- [R01HL101200]
- [R01GM129074]
- [R01HL146673]
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The alternate splicing of VEGF-A produces pro- and anti-angiogenic isoforms, offering new therapeutic opportunities for PAD treatment. Understanding these isoforms may lead to novel signaling pathways that enhance future therapeutics in PAD. Inhibiting specific anti-angiogenic VEGF-A isoforms has shown promising results in promoting perfusion recovery in PAD.
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
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