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Updated: Nov 2, 2025
Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
Peripheral vascular disease: preclinical models and emerging therapeutic targeting of the vascular endothelial growth
Vijay Chaitanya Ganta1, Brian H Annex1
1Department of Medicine and Vascular Biology Center, Augusta University, Augusta, GA, USA.
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.
Insights
Targeting specific anti-angiogenic VEGF-A isoforms in peripheral arterial disease (PAD) shows promise. Inhibiting these isoforms in ischemic muscle may improve blood flow and offers new therapeutic avenues for PAD.
Area of Science:
- Molecular biology
- Angiogenesis research
- Vascular biology
Background:
- Vascular endothelial growth factor (VEGF)-A is a key target for peripheral arterial disease (PAD) due to its role in angiogenesis.
- Previous VEGF-A clinical trials for PAD yielded no therapeutic benefit, indicating a gap in understanding VEGF-A biology and ischemic angiogenesis.
- VEGF-A undergoes alternate splicing, producing pro- and anti-angiogenic isoforms that differ by a six-amino acid switch.
Purpose of the Study:
- To explore the predicted mechanism of anti-angiogenic VEGF-A isoforms inhibiting angiogenesis.
- To investigate unexpected mechanisms of action for these isoforms.
- To identify novel signaling pathways revealed by these mechanisms for enhanced PAD therapeutics.
Main Methods:
- Literature search focusing on VEGF-A isoforms, angiogenesis inhibition, and novel signaling pathways.
- Analysis of preclinical data on inhibiting anti-angiogenic VEGF-A isoforms in ischemic muscle.
- Review of research on VEGF receptor-ligand interactions and their modulation.
Main Results:
- Inhibition of a specific anti-angiogenic VEGF-A isoform in preclinical models of PAD promotes perfusion recovery in ischemic muscle.
- Understanding the distinct roles of VEGF-A isoforms offers new insights into the failure of previous VEGF-A clinical trials.
- Novel signaling pathways influenced by VEGF-A isoform modulation have been identified.
Conclusions:
- Targeting specific anti-angiogenic VEGF-A isoforms presents a promising therapeutic strategy for PAD.
- Further research into isoform production and VEGF receptor-ligand interactions can accelerate clinical progress for PAD treatment.
- This approach offers new therapeutic opportunities for improving perfusion in PAD patients.
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