TY - JOUR
T1 - Fibronectin-mediated inflammatory signaling through integrin α5 in vascular remodeling
AU - Budatha, Madhusudhan
AU - Zhang, Jiasheng
AU - Schwartz, Martin A.
N1 - Funding Information:
We thank Tristan P. Driscoll, FAMU—FSU (Florida A&M University - Florida State University) College of Engineering, for advice on statistical analysis. Lipid analysis was done by the Yale Mouse Phenotypic Center. M.B. designed the study, performed all experiments, and analyzed data and wrote the article. M.B. performed most of the studies at Yale and completed the analysis at University of Texas Health Sciences, San Antonio. J.Z. performed the mouse surgeries. M.A.S. initiated the project, co-wrote the article, and provided financial support.
Publisher Copyright:
© 2021 The Authors.
PY - 2021/9/7
Y1 - 2021/9/7
N2 - BACKGROUND: Adhesion of vascular endothelial cells to the underlying basement membrane potently modulates endothelial cells to cells’ inflammatory activation. The normal basement membrane proteins laminin and collagen IV attenuate inflammatory signaling in part through integrin α2β1. In contrast, fibronectin, the provisional matrix protein found in injured, remodeling or inflamed vessels, sensitizes endothelial cells to inflammatory stimuli through integrins α5β1and and αvβ3. A chimeric integrin in which the cytoplasmic domain of α5 is replaced with that of α2 pairs with β1 and binds fibronectin but signals like α2β1. METHODS AND RESULTS: Here, we examined mice in which integrin α5 is replaced with the α5/2 chimera, using the transverse aortic constriction and partial carotid ligation models of vessel remodeling. Following transverse aortic constriction and partial carotid ligation surgery, wild-type mice showed increased fibronectin deposition and expression of inflammatory markers, which were strongly attenuated in a5/2 mice. α5/2 mice also showed reduced artery wall hypertrophy in the transverse aortic constriction model and diminished inward remodeling in the partial carotid ligation model. Acute atherosclerosis after partial carotid ligation in hyperlipidemic ApoE− / − mice on a high fat diet was dramatically decreased in α5/2 mice. CONCLUSIONS: Fibronectin and integrin α5 signaling is a key element of pathological vascular remodeling in acute models of both hypertension and disturbed flow. These results underscore the key role for integrin α5 signaling in pathological vascular remodeling associated with hypertension and atherosclerosis and support its potential as a therapeutic target.
AB - BACKGROUND: Adhesion of vascular endothelial cells to the underlying basement membrane potently modulates endothelial cells to cells’ inflammatory activation. The normal basement membrane proteins laminin and collagen IV attenuate inflammatory signaling in part through integrin α2β1. In contrast, fibronectin, the provisional matrix protein found in injured, remodeling or inflamed vessels, sensitizes endothelial cells to inflammatory stimuli through integrins α5β1and and αvβ3. A chimeric integrin in which the cytoplasmic domain of α5 is replaced with that of α2 pairs with β1 and binds fibronectin but signals like α2β1. METHODS AND RESULTS: Here, we examined mice in which integrin α5 is replaced with the α5/2 chimera, using the transverse aortic constriction and partial carotid ligation models of vessel remodeling. Following transverse aortic constriction and partial carotid ligation surgery, wild-type mice showed increased fibronectin deposition and expression of inflammatory markers, which were strongly attenuated in a5/2 mice. α5/2 mice also showed reduced artery wall hypertrophy in the transverse aortic constriction model and diminished inward remodeling in the partial carotid ligation model. Acute atherosclerosis after partial carotid ligation in hyperlipidemic ApoE− / − mice on a high fat diet was dramatically decreased in α5/2 mice. CONCLUSIONS: Fibronectin and integrin α5 signaling is a key element of pathological vascular remodeling in acute models of both hypertension and disturbed flow. These results underscore the key role for integrin α5 signaling in pathological vascular remodeling associated with hypertension and atherosclerosis and support its potential as a therapeutic target.
KW - Artery wall remodeling
KW - Atherosclerosis
KW - Extracellular matrix
KW - Hypertension
KW - Inflammation
KW - Integrin signaling
KW - Transverse aortic constriction
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U2 - 10.1161/JAHA.121.021160
DO - 10.1161/JAHA.121.021160
M3 - Article
C2 - 34472370
AN - SCOPUS:85116171431
VL - 10
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 17
M1 - e021160
ER -