{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:10:14Z","timestamp":1784113814916,"version":"3.55.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Vascular smooth muscle cell (VSMC) recruitment and activation by vessel injury cause intimal hyperplasia (IH) and restenosis. Drug\u2010eluting stents releasing mTOR (mechanistic target of rapamycin) blockers (sirolimus, everolimus [EV]) improve surgery outcomes but exhibit nonspecific effects and poor efficacy in diseased vessels. Drug combinations targeting the multifactorial processes leading to IH could enhance efficacy and reduce toxicity. Our previous work showed that Kv1.3 channel blockers such as 5\u2010(4\u2010phenoxybutoxy)psoralen (PAP\u20101) prevented IH. Since Kv1.3 signaling works through the MEK\/ERK pathway, we hypothesize that PAP\u20101 and EV combination could improve antirestenotic therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">The effects of PAP\u20101, EV, and their combination on IH development were studied in\u00a0vivo using a carotid ligation mouse model and ex\u00a0vivo in organ culture of human vessels. Individually, both drugs inhibited vessel remodeling, but, surprisingly, their combination canceled these inhibitory effects. In primary human VSMCs cultures, the drug combination abolished the inhibition of cell migration but not cell proliferation, which was even potentiated. We uncovered a crosstalk between mTOR and MEK\/ERK pathways in VSMCs, centered on P70S6K activation. P70S6K phosphorylation levels correlated with IH development, even reproducing the differences in EV response between diabetic and nondiabetic samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">VSMC migration, rather than proliferation, mirrors PAP\u20101 and EV effects on IH development in vessels. Critically, we identify VSMC P70S6K phosphorylation as a surrogate marker for IH progression. The nonmonotonic responses of P70S6K activation to pathway blockers suggest the existence of a crosstalk element functioning as an exclusive NOR logic gate providing new insights for IH prevention strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.038358","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:59:15Z","timestamp":1746172755000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Vascular Smooth Muscle Cell Migration and P70S6K: Key Players in Intimal Hyperplasia Development"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8047-2865","authenticated-orcid":false,"given":"Sara","family":"Moreno\u2010Estar","sequence":"first","affiliation":[{"name":"Universidad de Valladolid","place":["Valladolid, Spain"]},{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM), CSIC","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6338-7738","authenticated-orcid":false,"given":"Pilar","family":"Cidad","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid","place":["Valladolid, Spain"]},{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM), CSIC","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3162-4807","authenticated-orcid":false,"given":"Marycarmen","family":"Arevalo\u2010Martinez","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid","place":["Valladolid, Spain"]},{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM), CSIC","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-5033","authenticated-orcid":false,"given":"Ana M.","family":"Portillo","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Matem\u00e1ticas","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2066-5160","authenticated-orcid":false,"given":"Marcos","family":"Sacristan\u2010Moraleda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Matem\u00e1ticas","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esperanza","family":"Alonso","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid","place":["Valladolid, Spain"]},{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM), CSIC","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3870-421X","authenticated-orcid":false,"given":"Jose R.","family":"Lopez\u2010Lopez","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid","place":["Valladolid, Spain"]},{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM), CSIC","place":["Valladolid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8540-8117","authenticated-orcid":false,"given":"M. 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