Disrupted NOS signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow

Sanjeev A. Datar, Wenhui Gong, Youping He, Michael Johengen, Rebecca J. Kameny, Gary W Raff, Emin Maltepe, Peter E. Oishi, Jeffrey R. Fineman

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Associated abnormalities of the lymphatic circulation are well described in congenital heart disease. However, their mechanisms remain poorly elucidated. Using a clinically relevant ovine model of a congenital cardiac defect with chronically increased pulmonary blood flow (shunt), we previously demonstrated that exposure to chronically elevated pulmonary lymph flow is associated with: 1) decreased bioavailable nitric oxide (NO) in pulmonary lymph; and 2) attenuated endothelium-dependent relaxation of thoracic duct rings, suggesting disrupted lymphatic endothelial NO signaling in shunt lambs. To further elucidate the mechanisms responsible for this altered NO signaling, primary lymphatic endothelial cells (LECs) were isolated from the efferent lymphatic of the caudal mediastinal node in 4-wk-old control and shunt lambs. We found that shunt LECs (n = 3) had decreased bioavailable NO and decreased endothelial nitric oxide synthase (eNOS) mRNA and protein expression compared with control LECs (n = 3). eNOS activity was also low in shunt LECs, but, interestingly, inducible nitric oxide synthase (iNOS) expression and activity were increased in shunt LECs, as were total cellular nitration, including eNOS-specific nitration, and accumulation of reactive oxygen species (ROS). Pharmacological inhibition of iNOS reduced ROS in shunt LECs to levels measured in control LECs. These data support the conclusion that NOS signaling is disrupted in the lymphatic endothelium of lambs exposed to chronically increased pulmonary blood and lymph flow and may contribute to decreased pulmonary lymphatic bioavailable NO.

Original languageEnglish (US)
Pages (from-to)H137-H145
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number1
StatePublished - Jul 1 2016


  • Nitric oxide signaling
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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