Wnts are endothelial cell-derived PKD1/PKD2-dependent autocrine/paracrine vasodilators

Wingless/Int-1 (Wnts) are secreted glycoproteins and canonical Frizzled receptor ligands. Recent evidence indicates that some Wnts, including Wnt9b and Wnt5a, bind to polycystin 1 (PKD1), a transmembrane protein which can couple to polycystin 2 (PKD2) to form a non-selective cation channel. The functional significance of Wnts binding to PKD1 is unclear. We tested the hypothesis that Wnts regulate arterial contractility, investigated the cellular source of vasoregulatory Wnts, and examined stimuli which activate Wnt secretion in the vasculature. Our data show that intravascular administration of Wnt9b or Wnt5a stimulates an endothelial cell PKD1- and PKD2-dependent vasodilation in pressurized resistance-size arteries. Wnt9b and Wnt5a are present in plasma and serum and intravenous administration rapidly stimulates a reduction in blood pressure which requires PKD1 in endothelial cells. Wnts activate a PKD1-dependent non-selective cation current in endothelial cells which stimulates endothelial nitric oxide synthase and small conductance Ca 2+ -activated K + channels to induce vasodilation. Intravascular flow stimulates angiotensin II type 1 (AT1) receptors, which require Gq/11 and Porcupine to activate Wnt9b and Wnt5a secretion in endothelial cells. These secreted Wnts activate endothelial cell PKD1/PKD2 signaling through autocrine/paracrine communication and contribute to flow-mediated vasodilation. In summary, we show that intravascular flow stimulates AT1 receptors, which activate Wnt9b and Wnt5a secretion in endothelial cells. Secreted Wnts activate PKD1/PKD2 channels on endothelial cells to induce autocrine/paracrine vasodilation and reduce blood pressure. This research was funded by grant NHLBI HL158846, HL155180, and HL166411. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.