{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Deng H"],"funding":["NHLBI NIH HHS","American Heart Association (American Heart Association, Inc.)"],"pagination":["785-798"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12306366"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["3(7)"],"pubmed_abstract":["Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease."],"journal":["Nature cardiovascular research"],"pubmed_title":["A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling."],"pmcid":["PMC12306366"],"funding_grant_id":["R01 HL135582","24CDA1268658","P01 HL107205"],"pubmed_authors":["Pi X","Zhang J","Schwartz MA","Wang Y","De Val S","Deng H","Joshi D"],"additional_accession":[]},"is_claimable":false,"name":"A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling.","description":"Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-03-27T16:08:06.621Z","creation":"2025-08-30T03:05:15.688Z"},"accession":"S-EPMC12306366","cross_references":{"pubmed":["39196179"],"doi":["10.1038/s44161-024-00496-y"]}}