{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T11:32:43Z","timestamp":1774351963816,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,20]]},"group-title":"Physiology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Wingless\/Int-1 (Wnts) proteins are 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. Here, we tested the hypothesis that Wnts act through PKD1\/PKD2 channels on endothelial cells (ECs) to regulate arterial contractility and blood pressure and investigated the cellular source and secretory regulation of vasoactive Wnt proteins.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    A wide variety of approaches, including inducible EC-specific PKD1 and PKD2 knockout mice, reverse-transcription polymerase chain reaction, Western blotting, immunofluorescence, pressurized artery myography, blood pressure measurements, patch-clamp electrophysiology,\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    Wnt and nitric oxide assays, and Wnt secretion assays.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Intravascular Wnt9b or Wnt5a administration stimulates an EC PKD1\/PKD2-dependent dilation in pressurized resistance-size arteries. Wnt9b and Wnt5a are present in serum and plasma and intravenous infusion rapidly stimulates a blood pressure reduction which requires EC PKD1. Wnts stimulate a PKD1-dependent non-selective cation current in ECs which through Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling activates endothelial nitric oxide synthase (eNOS) and small conductance Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -activated K\n                    <jats:sup>+<\/jats:sup>\n                    channels to induce vasodilation. Wnt9b acts solely via PKD1\/PKD2 channels, whereas Wnt5a stimulates signaling through PKD1\/PKD2, Frizzled-7 (Fzd-7), Dishevelled and c-Jun N-terminal kinase (JNK). Intravascular flow stimulates angiotensin II type 1 (AT1) receptors, which through G\n                    <jats:sub>q\/11<\/jats:sub>\n                    and Porcupine activate Wnt9b and Wnt5a secretion in ECs. Wnts secreted in response to flow activate PKD1\/PKD2 signaling in ECs and contribute to flow-mediated vasodilation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Intravascular flow activates AT1 receptors, which through G\n                    <jats:sub>q\/11<\/jats:sub>\n                    and Porcupine stimulate Wnt9b and Wnt5a secretion in ECs. Wnt9b activates PKD1\/PKD2 channels whereas Wnt5a stimulates both PKD1\/PKD2 and Fzd-7 in ECs to induce vasodilation. Wnts contribute to flow-mediated autocrine\/paracrine dilation and reduce blood pressure.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"712518v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.17.712518","type":"posted-content","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T16:00:17Z","timestamp":1774022417000},"source":"Crossref","is-referenced-by-count":0,"title":["Wnts are endothelial cell-derived PKD1\/PKD2-dependent autocrine\/paracrine vasodilators"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2570-8972","authenticated-orcid":false,"given":"Ulrich C.","family":"Mbiakop","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis TN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2875-0677","authenticated-orcid":false,"given":"Charles E.","family":"Mackay","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis TN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1831-7842","authenticated-orcid":false,"given":"Alejandro","family":"Mata-Daboin","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis TN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-575X","authenticated-orcid":false,"given":"Roberto Braz","family":"Pontes","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis TN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Dennis","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis TN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-3335","authenticated-orcid":false,"given":"Jonathan H.","family":"Jaggar","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis 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