{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T18:44:03Z","timestamp":1775933043890,"version":"3.50.1"},"posted":{"date-parts":[[2025,2,23]]},"group-title":"Pharmacology and Toxicology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T00:00:00Z","timestamp":1740268800000},"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":[[2025,2,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD)\n                    <jats:sup>1<\/jats:sup>\n                    and dementia\n                    <jats:sup>2<\/jats:sup>\n                    . Akin to anti-hypertensive and lipid-lowering drugs, arterial de-stiffening therapies could be beneficial at decreasing CVD risk. We previously discovered that enhanced cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributes to increased arterial stiffness\n                    <jats:sup>3<\/jats:sup>\n                    . In aortas and VSMCs, we previously found that decreased NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, caused downregulation of cGMP-dependent protein kinase I (cGKI) and of its target vasodilator-stimulated phosphoprotein (pVASP\n                    <jats:sup>S239<\/jats:sup>\n                    ), leading to increased cytoskeletal actin polymerization\n                    <jats:sup>3<\/jats:sup>\n                    . In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP\n                    <jats:sup>S239<\/jats:sup>\n                    and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Approach &amp; Results<\/jats:title>\n                  <jats:p>\n                    Cinaciguat administration (5 mg\/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness\n                    <jats:sup>4<\/jats:sup>\n                    , (1) decreased pulse wave velocity, the\n                    <jats:italic>in vivo<\/jats:italic>\n                    index of arterial stiffness, without affecting blood pressure, (2) increased aortic pVASP\n                    <jats:sup>S239<\/jats:sup>\n                    levels, and (3) decreased the ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 \u03bcmol\/L) increased pVASP\n                    <jats:sup>S239<\/jats:sup>\n                    levels and decreased the F\/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor \u03b1 (TNF\u03b1), used to mimic the inflammatory milieu of HFHS aortas. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKI\n                    <jats:sup>SMKO<\/jats:sup>\n                    ), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP, 1 \u03bcmol\/L), which also decreased VSMC stiffness\n                    <jats:italic>in vitro<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.17.638762","type":"posted-content","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T12:25:18Z","timestamp":1740313518000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Activation of NO-Sensitive Guanylyl Cyclase Ameliorates Obesity-Induced Arterial Stiffness"],"prefix":"10.64898","author":[{"given":"Enkhjargal","family":"Budbazar","sequence":"first","affiliation":[{"name":"Vascular Biology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aylin","family":"Balmes","sequence":"additional","affiliation":[{"name":"Institute of Applied Physics, University of T\u00fcbingen, 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