Abstract
The vasculature within a tumor is highly disordered both structurally and functionally. Endothelial cells that comprise the vasculature are poorly connected causing vessel leakage and exposing the endothelium to a hypoxic microenvironment. Therefore, most anti-angiogenic therapies are generally inefficient and result in acquired resistance to increased hypoxia due to elimination of the vasculature. Recent studies have explored the efficacy of targeting metabolic pathways in tumor cells in combination with anti-angiogenic therapy. However, the metabolic alterations of endothelial cells in response to hypoxia have been relatively unexplored. Here, we measured polar metabolite levels in microvascular endothelial cells exposed to short- and long-term hypoxia with the goal of identifying metabolic vulnerabilities that can be targeted to normalize tumor vasculature and improve drug delivery. We found that many amino acid-related metabolites were altered by hypoxia exposure, especially within alanine-aspartate-glutamate, serine-threonine, and cysteine-methionine metabolism. Additionally, there were significant changes in de novo pyrimidine synthesis as well as glutathione and taurine metabolism. These results provide key insights into the metabolic alterations that occur in endothelial cells in response to hypoxia, which serve as a foundation for future studies to develop therapies that lead to vessel normalization and more efficient drug delivery.
Highlights
The tumor vasculature is highly disordered with both dense regions of vessels and areas that lack vessels
Hypoxia alters the polar metabolite profile of endothelial cells In order to assess the effects of hypoxia on endothelial cells, we used HMEC-1, human dermal microvascular endothelial cells, which most closely mimic endothelial cells found in the tumor vasculature [43]
To examine the metabolic profile of HMEC-1 cells exposed to short-term hypoxia, we used targeted liquid chromatography tandem mass spectrometry (LC/MS-MS) to measure the levels of 265 polar metabolites in cells cultured in hypoxia for 48 hrs; 178 metabolites were detected in all samples (S1 Table)
Summary
The tumor vasculature is highly disordered with both dense regions of vessels and areas that lack vessels. This leads to inefficient blood flow and delivery of nutrients to a tumor, resulting in a microenvironment that is nutrient-poor and hypoxic [1,2,3]. The endothelial cells that comprise disordered vessels are not tightly connected, resulting in leaky vessels [4,5] and exposing endothelial cells to a hypoxic environment. This leakiness facilitates tumor cell intravasation and metastasis and significantly impedes efficient drug delivery to tumors.
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