Emily M Nordquist1,2,3, Punashi Dutta2,3, Karthik M Kodigepalli2,3, Carol Mattern2,3, Michael R McDermott4,5, Aaron J Trask4,5,6, Stephanie LaHaye7, Volkhard Lindner8, Joy Lincoln2,3. 1. Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus (E.M.N.). 2. Department of Pediatrics, Section of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee (E.M.N., P.D., K.M.K., C.M., J.L.). 3. The Herma Heart Institute, Children's Wisconsin, Milwaukee (E.M.N., P.D., K.M.K., C.M., J.L.). 4. Center for Cardiovascular Research (M.R.M., A.J.T.), The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH. 5. The Heart Center, Nationwide Children's Hospital, Columbus, OH (M.R.M., A.J.T.). 6. Department of Pediatrics, The Ohio State University, Columbus (A.J.T.). 7. The Institute for Genomic Medicine (S.L.), The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH. 8. Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (V.L.).
Abstract
OBJECTIVE: Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response to injury and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16-18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 (Tgfβ1) and the glycoprotein, collagen triple helix repeat containing 1 (Cthrc1). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. CONCLUSIONS: Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.
OBJECTIVE: Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response to injury and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16-18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 (Tgfβ1) and the glycoprotein, collagen triple helix repeat containing 1 (Cthrc1). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. CONCLUSIONS: Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.
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Authors: Anabela Bensimon-Brito; Srinath Ramkumar; Giulia L M Boezio; Stefan Guenther; Carsten Kuenne; Christian S M Helker; Héctor Sánchez-Iranzo; Dijana Iloska; Janett Piesker; Soni Pullamsetti; Nadia Mercader; Dimitris Beis; Didier Y R Stainier Journal: Dev Cell Date: 2019-11-27 Impact factor: 12.270