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BMC Systems Biology

, 2:77

First Online: 19 August 2008Received: 19 February 2008Accepted: 19 August 2008

Abstract

BackgroundAngiogenesis is a process by which new capillaries are formed from pre-existing blood vessels in physiological e.g., exercise, wound healing or pathological e.g., ischemic limb as in peripheral arterial disease, cancer contexts. This neovascular mechanism is mediated by the vascular endothelial growth factor VEGF family of cytokines. Although VEGF is often targeted in anti-angiogenic therapies, there is little knowledge about how its concentration may vary between tissues and the vascular system. A compartment model is constructed to study the VEGF distribution in the tissue including matrix-bound, cell surface receptor-bound and free VEGF isoforms and in the blood. We analyze the sensitivity of this distribution to the secretion rate, clearance rate and vascular permeability of VEGF.

ResultsWe find that, in a physiological context, VEGF concentration varies approximately linearly with the VEGF secretion rate. VEGF concentration in blood but not in tissue is dependent on the vascular permeability of healthy tissue. Model simulations suggest that relative VEGF increases are similar in blood and tissue during exercise and return to baseline within several hours. In a pathological context tumor, we find that blood VEGF concentration is relatively insensitive to increased vascular permeability in tumors, to the secretion rate of VEGF by tumors and to the clearance. However, it is sensitive to the vascular permeability in the healthy tissue. Finally, the VEGF distribution profile in healthy tissue reveals that about half of the VEGF is complexed with the receptor tyrosine kinase VEGFR2 and the co-receptor Neuropilin-1. In diseased tissues, this binding can be reduced to 15% while VEGF bound to the extracellular matrix and basement membranes increases.

ConclusionThe results are of importance for physiological conditions e.g., exercise and pathological conditions e.g., peripheral arterial disease, coronary artery disease, cancer. This mathematical model can serve as a tool for understanding the VEGF distribution in physiological and pathological contexts as well as a foundation to investigate pro- or anti-angiogenic strategies.

Electronic supplementary materialThe online version of this article doi:10.1186-1752-0509-2-77 contains supplementary material, which is available to authorized users.

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Autor: Marianne O Stefanini - Florence TH Wu - Feilim Mac Gabhann - Aleksander S Popel

Fuente: https://link.springer.com/



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