Theoretical modeling of tumor angiogenesis: the opposing effects of vascular endothelial growth factor and angiopoietin-2

• Published in: Physiology (Bethesda, Md.) Md.), 2024-05, Vol.39 (S1)
• Main Authors: Nguyen, Vivian, Secomb, Timothy
• Format: Article
• Language: English
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2024.39.S1.1536

Abstract only Tumor microvascular networks are highly unstable, disorganized structures that obstruct cancer therapeutics by poorly distributing blood flow and oxygen. The elevated release of vascular endothelial growth factor (VEGF) by solid tumors has been widely implicated in pathological angiogenesis, or the growth of new blood vessels. However, how VEGF overexpression leads to the malformation of vascular networks is incompletely understood. Angiopoietin-2 (Ang2) is a destabilization factor that has been shown to promote sprouting in the presence of VEGF with hypoxia, but regression in its absence. Here, we hypothesize that the tumor environment, which sustains VEGF production under conditions of normoxia, also promotes Ang2-induced regression. A theoretical model is developed representing the 3-dimensional growth, remodeling, and pruning of microvascular networks in early-stage tumors to investigate the combined effects of VEGF and Ang2. Oxygen transport by the growing vascular network is simulated. VEGF production is induced by hypoxia and also elevated independent of oxygen levels in the expanding tumor region. Angiogenesis is stimulated in response to elevated VEGF levels. The model predicts that the release of VEGF in normoxic regions without counteracting factors results in very high tumor vascular densities compared to normal tissue, which is not observed experimentally. Introducing the regressive effects of Ang2 limits vascular density and produces greater variability in oxygen levels in the tumor region. Vascular networks in the tumor generated from the model show comparable densities to surrounding tissue, in which an elevated rate of sprouting is balanced by Ang2-induced regression. In this state, continuous turnover of vessels is predicted, while a relatively constant vascular density is maintained. These simulations suggest that the destabilizing role of Ang2 is an important factor that should be included in theoretical models for tumor angiogenesis. While Ang2 activity is already targeted in a number of clinical trials, clarifying the dynamic role of Ang2 may help advance angiogenesis-based therapeutic approaches. Supported by NIH grant HL034555. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.