{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:10:22Z","timestamp":1789063822942,"version":"build-2803163510"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,6,19]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Dysfunction of endothelial cells manifests early in pulmonary arterial hypertension and represents a critical therapeutic target. Nevertheless, the limited efficacy of single-target interventions underscores the need for innovative strategies that enable precise therapeutic modulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>The TRPV4 (transient receptor potential vanilloid 4)-KCa2.3 (small-conductance calcium-activated potassium channel 3) interaction was validated in experimental pulmonary hypertension mice using co-immunoprecipitation and fluorescence (F\u00f6rster) resonance energy transfer. Based on structure-guided molecular docking, a small-molecule candidate, JNc-455, was rationally designed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Dissociation of the TRPV4-KCa2.3 complex was confirmed by both co-immunoprecipitation and fluorescence (F\u00f6rster) resonance energy transfer analyses in lung tissues from patients with pulmonary arterial hypertension and experimental pulmonary hypertension mice. Endothelial cell-specific recombinant adeno-associated virus-mediated disruption of the complex promoted both the initiation and progression of pulmonary hypertension in vivo. Guided by these findings, we developed a series of compounds aimed at restoring TRPV4-KCa2.3 coupling. Among them, JNc-455 demonstrated significant therapeutic efficacy without overt toxicity. However, this effect was absent in endothelial TRPV4-deficient mice (TRPV4\n                      <jats:sub>EC<\/jats:sub>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ), indicating that the action of JNc-455 critically depends on the structural integrity of the complex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study investigates the critical role of the TRPV4-KCa2.3 complex in pulmonary arterial hypertension and, based on these findings, facilitates drug development and screening, thereby identifying JNc-455 as a promising novel therapeutic candidate for pulmonary arterial hypertension.<\/jats:p>\n                  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