Wnt Proteins are Endothelial Cell-derived Autocrine PKD1/PKD2 Ligands which Elicit Vasodilation

Intravascular flow stimulates endothelial cells (ECs) to produce vasodilation, but the signaling mechanisms involved are poorly understood. We have previously shown that flow stimulates a surface polycystin 1 (PKD1) and polycystin 2 (PKD2) complex in ECs, leading to Ca 2+ influx which stimulates vasodilation. Here, we investigated the mechanisms by which flow stimulates PKD1/PKD2 in ECs. Wingless (Wnts) are cysteine-rich secreted glycoproteins. Several Wnts, including Wnt9b and Wnt5a, are PKD1 ligands. We used tamoxifen-inducible, endothelial cell-specific PKD1 ( Pkd1 ecKO) and PKD2 knockout ( Pkd2 ecKO ) mice to test the hypothesis that Wnt proteins elicit vasodilation through PKD1/PKD2 activation. Wnt9b activated a Gd 3+ -sensitive non-selective cation current (I Cat ) in ECs of Pkd1 fl/fl mice, but not in ECs of Pkd1 ecKO mice. Intraluminal application of recombinant Wnt9b or Wnt5a dilated pressurized (80 mmHg) mesenteric arteries of PKD1 fl/fl and PKD2 fl/fl mice. Vasodilation to Wnt9b and Wnt5a was attenuated in pressurized arteries of Pkd1 ecKO and Pkd2 ecKO mice. L-NNA, a nitric oxide synthase (NOS) inhibitor, and apamin, a small conductance Ca 2+ -activated K + (SK) channel inhibitor, attenuated vasodilation to Wnt9b in pressurized PKD1 fl/fl arteries. Intravenous Wnt9b infusion reduced mean arterial blood pressure in Pkd1 fl/fl mice and this blood pressure reduction was less in Pkd1 ecKO mice. WIF-1, a Wnt-binding protein, reduced flow-mediated vasodilation, suggesting that flow stimulates ECs to secrete Wnt proteins. Flow increased Wnt9b and Wnt5a secretion in mesenteric artery ECs. Losartan, an angiotensin II type 1 receptor (AGTR1) antagonist, AGTR1 knockdown using siRNA, YM-254890, a selective canonical G α /q inhibitor, and Wnt-C59, a Porcupine inhibitor, reduced flow-mediated Wnt9b and Wnt5a secretion in ECs. Losartan also attenuated flow-mediated vasodilation in pressurized mesenteric arteries of Pkd1 fl/fl mice, but not in Pkd1 ecKO mouse, arteries. Taken together, these findings suggest that flow stimulates AGTR1s, leading to Wnt9b and Wnt5a secretion. These secreted Wnt proteins bind in an autocrine manner to PKD1/PKD2 on ECs and activate eNOS and SK channels to induce 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 2025 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.