Selective and Marked Blockade of Endothelial Sprouting Behavior Using Paclitaxel and Related Pharmacologic Agents

Whether alterations in the microtubule cytoskeleton affect the ability of endothelial cells (ECs) to sprout and form branching networks of tubes was investigated in this study. Bioassays of human EC tubulogenesis, where both sprouting behavior and lumen formation can be rigorously evaluated, were us...

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Veröffentlicht in:The American journal of pathology 2021-12, Vol.191 (12), p.2245-2264
Hauptverfasser: Lin, Prisca K., Salvador, Jocelynda, Xie, Jun, Aguera, Kalia N., Koller, Gretchen M., Kemp, Scott S., Griffin, Courtney T., Davis, George E.
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container_end_page 2264
container_issue 12
container_start_page 2245
container_title The American journal of pathology
container_volume 191
creator Lin, Prisca K.
Salvador, Jocelynda
Xie, Jun
Aguera, Kalia N.
Koller, Gretchen M.
Kemp, Scott S.
Griffin, Courtney T.
Davis, George E.
description Whether alterations in the microtubule cytoskeleton affect the ability of endothelial cells (ECs) to sprout and form branching networks of tubes was investigated in this study. Bioassays of human EC tubulogenesis, where both sprouting behavior and lumen formation can be rigorously evaluated, were used to demonstrate that addition of the microtubule-stabilizing drugs, paclitaxel, docetaxel, ixabepilone, and epothilone B, completely interferes with EC tip cells and sprouting behavior, while allowing for EC lumen formation. In bioassays mimicking vasculogenesis using single or aggregated ECs, these drugs induce ring-like lumens from single cells or cyst-like spherical lumens from multicellular aggregates with no evidence of EC sprouting behavior. Remarkably, treatment of these cultures with a low dose of the microtubule-destabilizing drug, vinblastine, led to an identical result, with complete blockade of EC sprouting, but allowing for EC lumen formation. Administration of paclitaxel in vivo markedly interfered with angiogenic sprouting behavior in developing mouse retina, providing corroboration. These findings reveal novel biological activities for pharmacologic agents that are widely utilized in multidrug chemotherapeutic regimens for the treatment of human malignant cancers. Overall, this work demonstrates that manipulation of microtubule stability selectively interferes with the ability of ECs to sprout, a necessary step to initiate and form branched capillary tube networks.
doi_str_mv 10.1016/j.ajpath.2021.08.017
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These findings reveal novel biological activities for pharmacologic agents that are widely utilized in multidrug chemotherapeutic regimens for the treatment of human malignant cancers. 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source PubMed Central Free; MEDLINE; Elsevier ScienceDirect Journals Complete; EZB-FREE-00999 freely available EZB journals
subjects Angiogenesis Inhibitors - pharmacology
Animals
Blood Vessels - drug effects
Blood Vessels - growth & development
Cells, Cultured
Docetaxel - pharmacology
Endothelial Cells - cytology
Endothelial Cells - drug effects
Endothelial Cells - physiology
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - growth & development
Epothilones - pharmacology
Human Umbilical Vein Endothelial Cells - cytology
Human Umbilical Vein Endothelial Cells - drug effects
Human Umbilical Vein Endothelial Cells - physiology
Humans
Mice
Mice, Inbred C57BL
Morphogenesis - drug effects
Neovascularization, Pathologic - drug therapy
Neovascularization, Pathologic - pathology
Neovascularization, Physiologic - drug effects
Paclitaxel - analogs & derivatives
Paclitaxel - pharmacology
Regular
title Selective and Marked Blockade of Endothelial Sprouting Behavior Using Paclitaxel and Related Pharmacologic Agents
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