Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis.
BACKGROUND
Myocardial infarction causes irreversible tissue damage, leading to heart failure. We recently discovered that canonical Wnt signaling and the Wnt10b ligand are strongly induced in mouse hearts after infarction. Wnt10b regulates cell fate in various organs, but its role in the heart is unknown.


OBJECTIVE
To investigate the effect of Wnt10b gain-of-function on cardiac repair mechanisms and to assess its potential to improve ventricular function after injury.


RESULTS
Histological and molecular analyses showed that Wnt10b is expressed in cardiomyocytes and localized in the intercalated discs of mouse and human hearts. After coronary artery ligation or cryoinjury in mice, Wnt10b is strongly and transiently induced in peri-infarct cardiomyocytes during granulation tissue formation. To determine the effect of Wnt10b on neovascularization and fibrosis, we generated a mouse line to increase endogenous Wnt10b levels in cardiomyocytes. We found that gain of Wnt10b function orchestrated a recovery phenotype characterized by robust neovascularization of the injury zone, less myofibroblasts, reduced scar size, and improved ventricular function compared with wild-type mice. Wnt10b stimulated expression of vascular endothelial growth factor receptor 2 in endothelial cells and angiopoietin-1 in vascular smooth muscle cells through nuclear factor-κB activation. These effects coordinated endothelial growth and smooth muscle cell recruitment, promoting robust formation of large, coronary-like blood vessels.


CONCLUSIONS
Wnt10b gain-of-function coordinates arterial formation and attenuates fibrosis in cardiac tissue after injury. Because generation of mature blood vessels is necessary for efficient perfusion, our findings could lead to novel strategies to optimize the inherent repair capacity of the heart and prevent the onset of heart failure.
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
David T
DT
Paik
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
Meena
M
Rai
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
Sergey
S
Ryzhov
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
Lehanna N
LN
Sanders
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
Omonigho
O
Aisagbonhi
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
Mitchell J
MJ
Funke
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.).
Igor
I
Feoktistov
From the Division of Cardiovascular Medicine, Department of Medicine (D.T.P., M.R., S.R., L.N.S., O.A., M.J.F., I.F., A.K.H.), Department of Cell and Developmental Biology (D.T.P., M.R., L.N.S., O.A., A.K.H.), and Department of Pharmacology, Vanderbilt University, Nashville, TN (I.F.); Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (S.R.); Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (O.A.); and Golden Rule Medical, Cincinnati, OH (M.J.F.). antonis.hatzopoulos@vanderbilt.edu.
Antonis K
AK
Hatzopoulos
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000378:metabolism*; D001808:Blood Vessels / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D042683:Angiopoietin-1; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C491119:WNT10B protein, human; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
Wnt signaling pathway; fibrosis; heart failure; myocardial infarction; neovascularization