Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury
- 14 October 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 41 (12), 2923-2942
- https://doi.org/10.1161/atvbaha.121.316450
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 to injury at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response 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.Keywords
This publication has 86 references indexed in Scilit:
- Endothelial nitric oxide signaling regulates Notch1 in aortic valve diseaseJournal of Molecular and Cellular Cardiology, 2013
- Embryological origin of the endocardium and derived valve progenitor cells: From developmental biology to stem cell-based valve repairBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013
- The evolving epidemiology of valvular aortic stenosis. The Tromsø StudyHeart, 2012
- Heart Disease and Stroke Statistics—2012 UpdateCirculation, 2012
- Recruitment of bone marrow-derived valve interstitial cells is a normal homeostatic processJournal of Molecular and Cellular Cardiology, 2011
- Roles of Matrix Metalloproteinases in Flow-Induced Outward Vascular RemodelingJournal of Cerebral Blood Flow & Metabolism, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Cthrc1 Is a Novel Inhibitor of Transforming Growth Factor-β Signaling and Neointimal Lesion FormationCirculation Research, 2007
- Aortic valve sclerosis is associatedwith systemic endothelial dysfunctionJournal of the American College of Cardiology, 2003
- Surface topography of stenotic aortic valves by scanning electron microscopy.Circulation, 1980