{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:15:40Z","timestamp":1788257740057,"version":"build-2803163510"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Aldosterone induces rapid, non-genomic vasodilation of the rat mesenteric vasculature, and mineralocorticoid receptor (MR) antagonists are widely used in cardiovascular disease, yet their pharmacological profiles beyond classical MR blockade remain unclear. We examined whether the G protein-coupled estrogen receptor (GPER\/GPR30), functionally coupled to the epidermal growth factor receptor (EGFR), accounts for the rapid endothelial nitric oxide (NO) component of aldosterone action, and whether MR antagonists display intrinsic GPER-linked activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Aldosterone-induced vasodilation was assessed in isolated perfused rat mesenteric arterial beds precontracted with noradrenaline, and NO production was quantified in primary mesenteric endothelial cell cultures by DAF-FM fluorescence with validated vehicle controls. The mechanisms engaged by spironolactone, eplerenone and finerenone were interrogated with selective pharmacological tools and by endothelium removal. Ligand recognition was explored by molecular docking in a comparative model of the rat GPER built on the human GPER cryo-EM template.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Aldosterone elicited concentration-dependent endothelial NO production (EC\n                      <jats:sub>50<\/jats:sub>\n                      = 2.26 \u00b1 0.3 nM) and vasodilation (EC\n                      <jats:sub>50<\/jats:sub>\n                      = 0.9 \u00b1 0.2 nM) that were closely correlated (R\n                      <jats:sup>2<\/jats:sup>\n                      = 0.969, p &amp;lt; 0.01). All three MR antagonists blocked the aldosterone responses, yet each also evoked intrinsic, concentration-dependent NO production in the absence of aldosterone, eplerenone and spironolactone showing greater intrinsic efficacy than finerenone. Pretreatment with 100 nM of the GPER antagonist G-36 or 100 nM AG-1478 significantly reduced both aldosterone-induced DAF-NO signaling and vasodilation, whereas endothelium removal or L-NAME converted vasodilation into vasoconstriction. Aldosterone signaling additionally required PI3K, PKA and IP\n                      <jats:sub>3<\/jats:sub>\n                      receptor-gated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      mobilization. Docking identified plausible receptor-engaging poses, with steroidal ligands converging on a shared cavity and finerenone adopting a distinct binding mode.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>MR antagonists elicit endothelial NO production through a G-36-sensitive, GPER-linked pathway functionally coupled to EGFR signaling, rather than acting as pure competitive antagonists in this context. Because recent cryo-EM work reveals a non-canonical extracellular GPER architecture, the docking results are interpreted as structurally plausible interaction scenarios rather than definitive orthosteric assignments; whether the behaviour reflects direct partial agonism at GPER or an indirect, GPER-dependent mechanism remains to be established by direct-binding studies. These findings expand current understanding of MR antagonist pharmacology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1891002","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:39:35Z","timestamp":1788255575000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["GPER and EGFR cross-talk highlight aldosterone- and MR antagonist-induced NO production in cultured endothelial cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Renata","family":"Paredes","sequence":"first","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda, Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Ver\u00f3nica","family":"Donoso","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda, Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos F.","family":"Lagos","sequence":"additional","affiliation":[{"name":"Chemical Biology & Drug Discovery Lab, Escuela de Qu\u00edmica y Farmacia, Facultad de Ciencias, Universidad San Sebasti\u00e1n","place":["Santiago, Chile"]},{"name":"Centro Basal Ciencia & Vida, Fundaci\u00f3n Ciencia & Vida","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"Centro Biolog\u00eda Integrativa, Facultad de Ciencias, Universidad Mayor","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Acu\u00f1a-Castillo","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda, Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Valdes","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda, Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Constandil","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda, Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Huidobro-Toro","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda, Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1093\/eurheartj\/ehaa736","article-title":"Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine","volume":"42","author":"Agarwal","year":"2021","journal-title":"Eur. 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