Wnt signaling, a novel pathway regulating blood pressure? State of the art review

Abstract

Recent antihypertensive trials show conflicting results on blood pressure (BP) targets in patient populations with different metabolic profiles, with lowest benefit from tight BP control observed in patients with type 2 diabetes mellitus. This paradox could arise from the heterogeneity of study populations and underscores the importance of precision medicine initiatives towards understanding and treating hypertension. Wnt signaling pathways and genetic variations in its signaling peptides have been recently associated with metabolic syndrome, hypertension and diabetes, generating a breakthrough for advancement of precision medicine in the field of hypertension. We performed a review of PubMed for publications addressing the contributions of Wnt to BP regulation and hypertension. In addition, we performed a manual search of the reference lists for relevant articles, and included unpublished observations from our laboratory. There is emerging evidence for Wnt's role in BP regulation and its involvement in the pathogenesis of hypertension. Wnt signaling has pleiotropic effects on distinct pathways that involve vascular smooth muscle plasticity, and cardiac, renal, and neural physiology. Hypertension is a heterogeneous disease with unique molecular pathways regulating its response to therapy. Recognition of these pathways is a prerequisite to identify novel targets for drug development and personalizing medicine. A review of Wnt signaling reveals its emerging role in BP regulation and as a target for novel drug development that has the potential to transform the therapy of hypertension in specific populations.

Keywords: Blood pressure; Diabetes; Hypertension; Metabolic syndrome; Wnt; β-catenin.

Fig. 1

Wnt signaling pathways. (A) The canonical pathway is activated once Wnt binds to the frizzled (FZD) receptor and LRP-5/6 co-receptor, thus recruiting disheveled (DVL) protein that inhibits the β-catenin destruction complex. Consequently, β-catenin accumulates in the cytoplasm and diffuses into the nucleus, binds to other transcription factors and activates gene expression. The non-canonical pathways (A and B) do not involve β-catenin. The planar cell polarity pathway (B) is activated once Wnt binds to FZD and the RYK/ROR co-receptor recruiting DVL and resulting in activation of the Rho and Rac signaling cascades. This causes cytoskeletal modifications and alteration in gene expression via the JNK pathway. The calcium signaling non-canonical pathway (C) involves Wnt binding to a G-protein coupled FZD that results in activation of phopholipase C (PLC) and phosphodiesterase 6, this leads to inositol triphosphate (IP3) production and stimulation of intracellular calcium release. The calcium cascade involves activation of CAMKII, PKC and alteration in gene transcription via the calcineurin-NFAT mechanism.