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

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

KEYWORDS:

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

Article highlights

• Alternative splicing in VEGF-A 8^th exon, near its C-terminus, results in the formation of pro- or anti-angiogenic VEGF-A isoforms of the same amino acid length.

• The pre-existing paradigm would have suggested that the anti-angiogenic VEGF-A isoforms simply exert their effect by blocking pro-angiogenic VEGF-A induced VEGFR2 activation to inhibit angiogenesis

• Our recent studies have shown that anti-angiogenic VEGF-A isoforms are in fact agonists of VEGFR2 but antagonists of VEGFR1 and targeted ligand removal have unveiled novel VEGFR1 signaling pathways in PAD relevant conditions.

• In the ischemic endothelial cells, the anti-angiogenic VEGF-A isoform inhibits VEGFR1 signaling to directly decrease angiogenesis.

• In the ischemic macrophages, the anti-Angiogenic VEGF-A isoform inhibits VEGFR1 signaling to induce an M1-like phenotype which inhibits angiogenesis in a paracrine manner.

Declaration of interest

BH Annex is the founder of Merand Pharmaceuticals which is seeking to develop microRNAs for PAD. VC Ganta received a grant from Merand Pharm. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Annex BH is supported by [R01HL141325, R01HL148590, RO1HL150003, R01HL101200] (Popel, Johns Hopkins, PI), R01GM129074 (Mac Gabhann, Johns Hopkins, PI). Ganta VC is supported by R01HL146673.