Abstract
Angiogenesis is important for many physiological processes, diseases, and also regenerative medicine. Therapies that inhibit the vascular endothelial growth factor (VEGF) pathway have been used in the clinic for cancer and macular degeneration. In cancer applications, these treatments suffer from a “tumor escape phenomenon” where alternative pathways are upregulated and angiogenesis continues. The redundancy of angiogenesis regulation indicates the need for additional studies and new drug targets. We aimed to (i) identify novel and missing angiogenesis annotations and (ii) verify their significance to angiogenesis. To achieve these goals, we integrated the human interactome with known angiogenesis-annotated proteins to identify a set of 202 angiogenesis-associated proteins. Across endothelial cell lines, we found that a significant fraction of these proteins had highly perturbed gene expression during angiogenesis. After treatment with VEGF-A, we found increasing expression of HIF-1α, APP, HIV-1 tat interactive protein 2, and MEF2C, while endoglin, liprin β1 and HIF-2α had decreasing expression across three endothelial cell lines. The analysis showed differential regulation of HIF-1α and HIF-2α. The data also provided additional evidence for the role of endothelial cells in Alzheimer's disease.
Highlights
Angiogenesis has been implicated in a wide spectrum of diseases including cancer, age-related macular degeneration, rheumatoid arthritis, diabetic nephropathy, pathologic obesity, and asthma
To ensure that the first objective is satisfied, the basis for our search began with proteins known to be annotated with angiogenesis from the Gene Ontology database (GO)
We identified a set of 202 angiogenesis associated proteins
Summary
Angiogenesis has been implicated in a wide spectrum of diseases including cancer, age-related macular degeneration, rheumatoid arthritis, diabetic nephropathy, pathologic obesity, and asthma. Compounds that inhibit angiogenesis represent potential therapeutics for many diseases. Many compounds have entered clinical trials as modulators of angiogenesis. Targeting the vascular endothelial growth factor (VEGF) pathway has been the leading anti-angiogenic strategy in the clinic [3]. Other anti-angiogenic targets include integrins [4] and angiopoietin 1 [5]. While these therapies suppress new blood vessel growth for a period of time, anti-angiogenic therapies suffer from the upregulation of compensating pathways that circumvent the inhibited pathway. The field is in need of a comprehensive understanding of the proteins and pathways involved in angiogenesis
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