Single-Cell RNA Sequencing Reveals That Adaptation of Human Aortic Endothelial Cells to Antiproliferative Therapies Is Modulated by Flow-Induced Shear Stress
BACKGROUND: Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation.
METHODS: Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm2) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing.
RESULTS: We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies.
CONCLUSIONS: We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli.
| Errataetall: |
CommentIn: Arterioscler Thromb Vasc Biol. 2023 Dec;43(12):2282-2284. - PMID 37942613 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Arteriosclerosis, thrombosis, and vascular biology - 43(2023), 12 vom: 05. Dez., Seite 2265-2281 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Salazar-Martín, Antonio G [VerfasserIn] |
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| Links: |
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| Themen: |
Cardiovascular diseases |
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| Anmerkungen: |
Date Completed 24.11.2023 Date Revised 26.02.2024 published: Print-Electronic CommentIn: Arterioscler Thromb Vasc Biol. 2023 Dec;43(12):2282-2284. - PMID 37942613 Citation Status MEDLINE |
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| doi: |
10.1161/ATVBAHA.123.319283 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Single-Cell RNA Sequencing Reveals That Adaptation of Human Aortic Endothelial Cells to Antiproliferative Therapies Is Modulated by Flow-Induced Shear Stress |
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| 500 | |a CommentIn: Arterioscler Thromb Vasc Biol. 2023 Dec;43(12):2282-2284. - PMID 37942613 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation | ||
| 520 | |a METHODS: Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm2) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing | ||
| 520 | |a RESULTS: We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies | ||
| 520 | |a CONCLUSIONS: We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a cardiovascular diseases | |
| 650 | 4 | |a endothelial cells | |
| 650 | 4 | |a humans | |
| 650 | 4 | |a paclitaxel | |
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| 700 | 1 | |a Villanueva, Martin A |e verfasserin |4 aut | |
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| 700 | 1 | |a Shalek, Alex K |e verfasserin |4 aut | |
| 700 | 1 | |a Edelman, Elazer R |e verfasserin |4 aut | |
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