Frizzled 4 Regulates Arterial Network Organization Through Noncanonical Wnt/Planar Cell Polarity Signaling

Rationale: A growing body of evidence supports the hypothesis that the Wnt/planar cell polarity (PCP) pathway regulates endlothelial cell proliferation and angiogenesis, but the components that mediate this regulation remain elusive. Objective: We investigated the involvement of one of the receptors, Frizzled4 (Fzd4), in this process because its role has been implicated in retinal vascular development. Methods and Results: We found that loss of fzd4 function in mice results in a striking reduction and impairment of the distal small artery network in the heart and kidney. We report that loss of fzd4 decreases vascular cell proliferation and migration and decreases the ability of the endothelial cells to form tubes. We show that fzd4 deletion induces defects in the expression level of stable acetylated tubulin and in Golgi organization during migration. Deletion of fzd4 favors Wnt noncanonical AP1-dependent signaling, indicating that Fzd4 plays a pivotal role favoring PCP signaling. Our data further demonstrate that Fzd4 is predominantly localized on the top of the plasma membrane, where it preferentially induces Dv13 relocalization to promote its activation and a-tubulin recruitment during migration. In a pathological mouse angiogenic model, deletion of fzd4 impairs the angiogenic response and leads to the formation of a disorganized arterial network. Conclusions: These results suggest that Fzd4 is a major receptor involved in arterial formation and organization through a Wnt/PCP pathway. (Circ Res. 2012;110:47-58.)