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| Status |
Public on May 24, 2024 |
| Title |
A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cells (EC) sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Higher FSS induces vessel outward remodeling to return FSS to physiological levels, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS and suppressed at higher flow. The Smad1/5 pathway opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling. Here, we report that suppression of Smad1/5 at high FSS is mediated by elevated KLF2, which induces the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes. Thus, suppression of Smad1/5 is required for high FSS-mediated outward remodeling and is a potential therapeutic approach for ischemic disease.
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| Overall design |
Human umbilical vein endothelial cells (HUVECs) were transfected with Ctrl (siCtrl) or KLF2 (siKLF2) siRNA for 4 days, total RNA was extracted and subjected to RNAseq, n=4 samples for each group.
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| Contributor(s) |
Deng H |
| Citation(s) |
- Deng H, Zhang J, Wang Y, Joshi D et al. A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling. Nat Cardiovasc Res 2024 Jul;3(7):785-798. PMID: 39196179
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| <button class="button" id="geo2r_button">Analyze with GEO2R</button> <button class="button" id="download_button">Download RNA-seq counts</button> |
| Submission date |
May 18, 2024 |
| Last update date |
Aug 29, 2024 |
| Contact name |
Hanqiang Deng |
| E-mail(s) |
hanqiang.deng@yale.edu
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| Phone |
475 414 9546
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| Organization name |
Yale University
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| Department |
Yale Cardiovascular Research Center
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| Street address |
116 Court Street
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| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06511 |
| Country |
USA |
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