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Updated: May 27, 2026
Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
Frizzled 4 regulates arterial network organization through noncanonical Wnt/planar cell polarity signaling
Betty Descamps1, Raj Sewduth, Nancy Ferreira Tojais
1Inserm U1034, 125 Av du Haut lévèque, 33 600 Pessac, France.
Rationale:
A growing body of evidence supports the hypothesis that the Wnt/planar cell polarity (PCP) pathway regulates endothelial 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 Dvl3 relocalization to promote its activation and α-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.
Insights
Frizzled4 (Fzd4) is crucial for forming and organizing blood vessels via the Wnt/planar cell polarity (PCP) pathway. Loss of Fzd4 impairs vascular development, cell migration, and tube formation, highlighting its role in angiogenesis.
Area of Science:
- Vascular biology
- Cell signaling
- Developmental biology
Background:
- The Wnt/planar cell polarity (PCP) pathway is implicated in endothelial cell proliferation and angiogenesis.
- Key mediators of Wnt/PCP pathway regulation in vascular development are not fully understood.
Purpose of the Study:
- To investigate the role of Frizzled4 (Fzd4), a Wnt receptor, in vascular development and angiogenesis.
- To elucidate the molecular mechanisms by which Fzd4 influences endothelial cell behavior.
Main Methods:
- Utilized Fzd4 knockout mouse models to study vascular development in heart and kidney.
- Assessed vascular cell proliferation, migration, and tube formation.
- Analyzed the expression of acetylated tubulin and Golgi organization.
- Investigated Wnt signaling pathway activation (AP1-dependent).
- Examined Fzd4 localization and its effect on Dvl3 and α-tubulin.
Main Results:
- Loss of Fzd4 function in mice led to reduced and impaired distal small artery networks.
- Fzd4 deficiency decreased vascular cell proliferation, migration, and endothelial tube formation.
- Fzd4 deletion disrupted acetylated tubulin levels and Golgi organization during migration.
- Fzd4 deficiency promoted Wnt noncanonical AP1-dependent signaling.
- Fzd4 localized to the plasma membrane, promoting Dvl3 relocalization and α-tubulin recruitment.
- Fzd4 deletion impaired the angiogenic response in a pathological model, causing disorganized arterial networks.
Conclusions:
- Fzd4 is a critical receptor in arterial formation and organization.
- Fzd4 functions through the Wnt/PCP pathway to regulate vascular development.
- Fzd4 plays a pivotal role in promoting PCP signaling essential for angiogenesis.
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