Targeting the Wnt signaling pathways in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease.

Figure 1

The Wnt canonical and non-canonical pathways. (a) The Wnt/β-catenin(bC) pathway. In the normal steady state, bC is targeted for degradation by a cytoplasmic APC/Axin/GSK-3β protein complex. Once bound to this complex, bC is targeted by coordinated phosphorylation by CK1/APC/Axin/GSK-3β-complex leading to its ubiquitination and proteasomal degradation. However, when the Wnt ligand binds to Frizzled/LRP5/6 co-receptors, subsequently triggers activation of Dvl followed by releasing bC from an inhibitory APC/Axin/GSK-3β-complex. bC translocates into the nucleus and activates genes involved in cell proliferation, survival and differentiation. (b). The Wnt/PCP pathway. When the Wnt ligand binds to Wnt/PCP receptor complex, Dvl is responsible for initiating the signaling cascade that culminates in the activation of the small GTPases Rac, Rho and cdc42. Once activated, these proteins trigger cytoskeletal rearrangements which regulate cell motility and polarity.

Figure 2

Proposed models. (a). After vascular injury, Wnt/ bC regulates cell proliferation/regeneration while Wnt/PCP regulates cell migration on the injure sites. Wnt signaling pathways play a major role in preserving pulmonary vascular homeostasis. (b) In PAH, altered Wnt pathway activation could lead to progressive loss of small vessels and allow excessive PASMC growth.