{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T07:10:57Z","timestamp":1770102657481,"version":"3.49.0"},"reference-count":56,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:p> We have previously shown decreased pulmonary lymph flow in our lamb model of chronically increased pulmonary blood flow, created by the in utero placement of an 8-mm aortopulmonary shunt. The purpose of this study was to test the hypothesis that abnormal lymphatic function in shunt lambs is due to impaired lymphatic endothelial nitric oxide (NO)-cGMP signaling resulting in increased lymphatic vascular constriction and\/or impaired relaxation. Thoracic duct rings were isolated from 4-wk-old shunt ( n = 7) and normal ( n = 7) lambs to determine length-tension properties, vascular reactivity, and endothelial NO synthase protein. At baseline, shunt thoracic duct rings had 2.6-fold higher peak to peak tension and a 2-fold increase in the strength of contractions compared with normal rings ( P &lt; 0.05). In response to norepinephrine, shunt thoracic duct rings had a 2.4-fold increase in vascular tone compared with normal rings ( P &lt; 0.05) and impaired relaxation in response to the endothelium-dependent dilator acetylcholine (63% vs. 13%, P &lt; 0.05). In vivo, inhaled NO (40 ppm) increased pulmonary lymph flow (normalized for resistance) \u223c1.5-fold in both normal and shunt lambs ( P &lt; 0.05). Inhaled NO exposure increased bioavailable NO [nitrite\/nitrate (NO<jats:sub> x<\/jats:sub>); \u223c2.5-fold in normal lambs and \u223c3.4-fold in shunt lambs] and cGMP (\u223c2.5-fold in both) in the pulmonary lymph effluent ( P &lt; 0.05). Chronic exposure to increased pulmonary blood flow is associated with pulmonary lymphatic endothelial injury that disrupts NO-cGMP signaling, leading to increased resting vasoconstriction, increased maximal strength of contraction, and impaired endothelium-dependent relaxation. Inhaled NO increases pulmonary lymph NO<jats:sub> x<\/jats:sub> and cGMP levels and pulmonary lymph flow in normal and shunt lambs. Therapies that augment NO-cGMP signaling within the lymphatic system may provide benefits, warranting further study. <\/jats:p>","DOI":"10.1152\/ajpheart.00841.2013","type":"journal-article","created":{"date-parts":[[2014,2,15]],"date-time":"2014-02-15T04:54:25Z","timestamp":1392440065000},"page":"H954-H962","source":"Crossref","is-referenced-by-count":15,"title":["Altered reactivity and nitric oxide signaling in the isolated thoracic duct from an ovine model of congenital heart disease with increased pulmonary blood flow"],"prefix":"10.1152","volume":"306","author":[{"given":"Sanjeev A.","family":"Datar","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California, San Francisco, California;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter E.","family":"Oishi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Francisco, California;"},{"name":"Cardiovascular Research Institute, 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