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Combinations of pro‐angiogenic therapies targeting VEGF and VEGF receptors outperform monotherapies in computational models of human skeletal muscle.
Author(s) -
Mac Gabhann Feilim,
Popel Aleksander S
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1214-c
Subject(s) - angiogenesis , receptor , medicine , downregulation and upregulation , vascular endothelial growth factor , cancer research , kinase insert domain receptor , in vivo , vascular endothelial growth factor a , vegf receptors , endocrinology , pharmacology , biology , biochemistry , gene , microbiology and biotechnology
Although vascular endothelial growth factor (VEGF) has been proposed as a possible therapy for ischemic diseases such as peripheral arterial disease (PAD), clinical trials of both VEGF gene delivery and VEGF protein delivery have failed. The standard therapy for PAD is exercise training, during which both VEGF secretion and VEGF receptor expression are upregulated. We hypothesized that simultaneous upregulation of both VEGF and its receptors could improve on VEGF monotherapy. To understand the ineffectiveness of VEGF monotherapy and the success of exercise training, we developed a model of VEGF transport in tissues in vivo. These simulations focus in particular on human vastus lateralis muscle, and tissue anatomy is included as tissue‐specific geometrical parameters (fiber size, shape and surface area; interstitial volume; vessel size distribution and length). Three VEGF receptors are included: VEGFR1, VEGFR2 and the non‐signaling co‐receptor Neuropilin‐1. By changing the expression levels of these receptors, pro‐angiogenic signaling in vivo is affected. While VEGF secretion alone demonstrates some increase in signaling, it is divided between the pro‐angiogenic VEGFR2 signaling and anti‐angiogenic VEGFR1 signaling. Combinations of VEGF and VEGFR‐targeted therapies are predicted to be particularly effective in increasing the pro‐angiogenesis signal.