Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis

Abstract

Rationale Myocardial infarction causes irreversible tissue damage, leading to heart failure (HF). 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 assess its potential to improve ventricular function after injury. Methods and 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 area 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 to wild-type mice. Wnt10b stimulated expression of Vascular Endothelial Growth Factor Receptor 2 (Vegfr-2) in endothelial cells and Angiopoietin-1 in vascular smooth muscle cells through NF-κB activation. These effects coordinated endothelial growth and smooth muscle cell recruitment, promoting robust formation of large, coronary-like blood vessels. Conclusion 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 HF.

Temporary, Systemic Inhibition of the WNT/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct

“…Moreover, in the context of complicated [5,9,13,16,32] and multifaceted roles of the WNT pathway in infarct repair in the existing literature, our data may speak to the potential of temporally regulated scalable pharmacologic WNT inhibition in reconciling the discordant observations based on genetic models [6,7,14] of WNT modulation. With additional details on the mechanism-of-action and safety data emerging with continuing studies, and ongoing clinical trials [23], GNF-6231 and the new class of Porcupine inhibitors hold significant potential as effective therapeutics for cardiac regeneration.…”

“…In this study, we focused exclusively on the effects of Porcupine inhibition through the β-catenin-dependent arm of the WNT pathway based on the significant body of literature suggesting a critical and complicated role—both maladaptive [6,7,30], and in some cases pro-reparative [13,14,16]—for this signaling cascade in infarct pathology. However, since GNF-6231 targets Porcupine, its effects independent of canonical WNT pathway may also be important.…”

“…Paik et al [13] showed that gain-of-function of a canonical WNT ligand, WNT 10b, in cardiomyocytes can orchestrate recovery by augmenting neovascularization. Interruption of WNT 1/β-catenin signals specifically in the epicardium through β-catenin deletion was reported to impede adaptive pro-fibrotic response [14,15], whereas post-infarct injection of adenoviral vector with constitutively active β-catenin reduced infarct size by boosting cardiomyocyte survival, and granulation tissue formation by myofibroblasts [16].…”

BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction

“…Using typical inflammatory gene markers, such as Il-1β and E-selectin , and markers of granulation tissue formation and fibrosis, such as Tgfβ1 and alpha Smooth Muscle Actin (α Sma ), we determined that pro-inflammatory genes are induced early and peak at days 1–2 after MI, whereas fibrosis genes are induced at day 5, as expected. 4,6,8 Gene induction of inflammatory genes returned to baseline levels between days 3 to 5, whereas Tgfβ1 expression returned to baseline at day 21. α Sma levels declined, but were still detectable at day 21, reflecting the presence of myofibroblasts during the scar maturation phase (Figure 1A). …”

“…6 We have recently demonstrated that canonical Wnt signaling activation after MI attenuates fibrosis and promotes arteriole formation and cardiogenesis, suggesting that developmental pathways, critical for embryonic cardiac development, are re-activated after injury in the adult heart to regulate tissue repair. 7,8 …”