Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury. Arterioscler Thromb Vasc Biol 2021 Dec;41(12):2923-2942
Date
10/15/2021Pubmed ID
34645278Pubmed Central ID
PMC8612994DOI
10.1161/ATVBAHA.121.316450Scopus ID
2-s2.0-85122166832 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Nordquist EM, Dutta P, Kodigepalli KM, Mattern C, McDermott MR, Trask AJ, LaHaye S, Lindner V, Lincoln JAuthor
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgingAnimals
Aortic Diseases
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Endothelium, Vascular
Extracellular Matrix
Extracellular Matrix Proteins
Female
Male
Mice
Mice, Inbred C57BL
Sequence Analysis, RNA
Signal Transduction
Swine
Transforming Growth Factor beta1
Up-Regulation
