Issue 1, 2018

A computational analysis of pro-angiogenic therapies for peripheral artery disease

Abstract

Inducing therapeutic angiogenesis to effectively form hierarchical, non-leaky networks of perfused vessels in tissue engineering applications and ischemic disease remains an unmet challenge, despite extensive research and multiple clinical trials. Here, we use a previously-developed, multi-scale, computational systems pharmacology model of human peripheral artery disease to screen a diverse array of promising pro-angiogenic strategies, including gene therapy, biomaterials, and antibodies. Our previously-validated model explicitly accounts for VEGF immobilization, Neuropilin-1 binding, and weak activation of VEGF receptor 2 (VEGFR2) by the “VEGFxxxb” isoforms. First, we examine biomaterial-based delivery of VEGF engineered for increased affinity to the extracellular matrix. We show that these constructs maintain VEGF close to physiological levels and extend the duration of VEGFR2 activation. We demonstrate the importance of sub-saturating VEGF dosing to prevent angioma formation. Second, we examine the potential of ligand- or receptor-based gene therapy to normalize VEGF receptor signaling. Third, we explore the potential for antibody-based pro-angiogenic therapy. Our model supports recent observations that improvement in perfusion following treatment with anti-VEGF165b in mice is mediated by VEGF-receptor 1, not VEGFR2. Surprisingly, the model predicts that the approved anti-VEGF cancer drug, bevacizumab, may actually improve signaling of both VEGFR1 and VEGFR2 via a novel ‘antibody swapping’ effect that we demonstrate here. Altogether, this model provides insight into the mechanisms of action of several classes of pro-angiogenic strategies within the context of the complex molecular and physiological processes occurring in vivo. We identify molecular signaling similarities between promising approaches and key differences between promising and ineffective strategies.

Graphical abstract: A computational analysis of pro-angiogenic therapies for peripheral artery disease

Supplementary files

Article information

Article type
Paper
Submitted
16 Dec 2017
Accepted
03 Jan 2018
First published
03 Jan 2018

Integr. Biol., 2018,10, 18-33

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