{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:00:21Z","timestamp":1792522821525,"version":"4.5.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Accumulating evidence suggests that hydrogen sulfide ( H\n              <jats:sub>2<\/jats:sub>\n              S ), an endogenously produced gaseous molecule, plays a critical role in the regulation of cardiovascular homeostasis. However, little is known about its role in lymphangiogenesis. Thus, the current study aimed to investigate the involvement of H\n              <jats:sub>2<\/jats:sub>\n              S in lymphatic vessel growth and lymphedema resolution using a murine model and assess the underlying mechanisms.\n            <\/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\">\n              A murine model of tail lymphedema was created both in wild\u2010type mice and cystathionine \u03b3\u2010lyase\u2013knockout mice, to evaluate lymphedema up to 28\u2009days after lymphatic ablation. Cystathionine \u03b3\u2010lyase\u2013knockout mice had greater tail diameters than wild\u2010type mice, and this phenomenon was associated with the inhibition of reparative lymphangiogenesis at the site of lymphatic ablation. In contrast, the administration of an H\n              <jats:sub>2<\/jats:sub>\n              S donor, diallyl trisulfide, ameliorated lymphedema by inducing the formation of a considerable number of lymphatic vessels at the injured sites in the tails. In vitro experiments using human lymphatic endothelial cells revealed that diallyl trisulfide promoted their proliferation and differentiation into tube\u2010like structures by enhancing Akt (protein kinase B) phosphorylation in a concentration\u2010dependent manner. The blockade of Akt activation negated the diallyl trisulfide\u2013induced prolymphangiogenic responses in lymphatic endothelial cells. Furthermore, the effects of diallyl trisulfide treatment on lymphangiogenesis in the tail lymphedema model were also negated by the inhibition of phosphoinositide 3'\u2010kinase (P13K)\/Akt\u00a0signaling.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              H\n              <jats:sub>2<\/jats:sub>\n              S promotes reparative lymphatic vessel growth and ameliorates secondary lymphedema, at least in part, through the activation of the Akt pathway in lymphatic endothelial cells. As such, H\n              <jats:sub>2<\/jats:sub>\n              S donors could be used as therapeutics against refractory secondary lymphedema.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.026889","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T10:30:44Z","timestamp":1666780244000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Hydrogen Sulfide Attenuates Lymphedema Via the Induction of Lymphangiogenesis Through a PI3K\/Akt\u2010Dependent Mechanism"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8115-6837","authenticated-orcid":false,"given":"Junya","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Cardiology Nagoya University Graduate School of Medicine| Nagoya 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