A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling.

Deng, Hanqiang; Zhang, Jiasheng; Wang, Yewei; Joshi, Divyesh; Pi, Xinchun; De Val, Sarah; Schwartz, Martin A

Deng, Hanqiang; Zhang, Jiasheng; Wang, Yewei; Joshi, Divyesh; Pi, Xinchun; De Val, Sarah; Schwartz, Martin A.

Afiliación

Deng H; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.
Zhang J; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Wang Y; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.
Joshi D; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Pi X; Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
De Val S; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.
Schwartz MA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.

Nat Cardiovasc Res ; 3(7): 785-798, 2024 Jul.

Article en En | MEDLINE | ID: mdl-39196179

ABSTRACT

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.

Asunto(s)

Factores de Transcripción de Tipo Kruppel; Proteína Smad1; Proteína Smad5; Remodelación Vascular; Animales; Proteína Smad5/metabolismo; Proteína Smad5/genética; Proteína Smad1/metabolismo; Proteína Smad1/genética; Factores de Transcripción de Tipo Kruppel/metabolismo; Factores de Transcripción de Tipo Kruppel/genética; Remodelación Vascular/fisiología; Humanos; Estrés Mecánico; Modelos Animales de Enfermedad; Ratones; Ratones Endogámicos C57BL; Masculino; Células Endoteliales/metabolismo; Células Endoteliales de la Vena Umbilical Humana; Ratones Noqueados; Proteínas Proto-Oncogénicas c-akt/metabolismo; Mecanotransducción Celular; Células Cultivadas; Transducción de Señal

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Smad1 / Proteína Smad5 / Factores de Transcripción de Tipo Kruppel / Remodelación Vascular Límite: Animals / Humans / Male Idioma: En Revista: Nat Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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