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.
abstract: 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 < 0.05). In response to norepinephrine, shunt thoracic duct rings had a 2.4-fold increase in vascular tone compared with normal rings (P < 0.05) and impaired relaxation in response to the endothelium-dependent dilator acetylcholine (63% vs. 13%, P < 0.05). In vivo, inhaled NO (40 ppm) increased pulmonary lymph flow (normalized for resistance) ∼1.5-fold in both normal and shunt lambs (P < 0.05). Inhaled NO exposure increased bioavailable NO [nitrite/nitrate (NOx); ∼2.5-fold in normal lambs and ∼3.4-fold in shunt lambs] and cGMP (∼2.5-fold in both) in the pulmonary lymph effluent (P < 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 NOx 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.
authors: Department of Pediatrics, University of California, San Francisco, California;
authors: Sanjeev A
authors: SA
authors: Datar
authors: Peter E
authors: PE
authors: Oishi
authors: Wenhui
authors: W
authors: Gong
authors: Stephen H
authors: SH
authors: Bennett
authors: Christine E
authors: CE
authors: Sun
authors: Michael
authors: M
authors: Johengen
authors: Jun
authors: J
authors: Maki
authors: Rebecca C
authors: RC
authors: Johnson
authors: Gary W
authors: GW
authors: Raff
authors: Jeffrey R
authors: JR
authors: Fineman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001783:Blood Flow Velocity; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000378:metabolism* / Q000503:physiopathology; D008196:Lymph / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000503:physiopathology*; D011652:Pulmonary Circulation; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D013897:Thoracic Duct / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D006152:Cyclic GMP; D009638:Norepinephrine
keywords: lymphatic endothelial function; nitric oxide; nitric oxide-cGMP signaling