Blunted flow-mediated responses and diminished nitric oxide synthase expression in lymphatic thoracic ducts of a rat model of metabolic syndrome

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 310; no. 3; pp. H385 - H393
• Main Authors: Zawieja, Scott D, Gasheva, Olga, Zawieja, David C, Muthuchamy, Mariappan
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2016
• Subjects: Animals; Antioxidants - pharmacology; Cyclic N-Oxides - pharmacology; Endothelium, Lymphatic - drug effects; Endothelium, Lymphatic - metabolism; Endothelium, Lymphatic - physiopathology; Enzyme Inhibitors - pharmacology; Insulin resistance; Male; Metabolic syndrome; Metabolic Syndrome - metabolism; Metabolic Syndrome - physiopathology; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - metabolism; Oxygen; Penicillamine - analogs & derivatives; Penicillamine - pharmacology; Pulsatile Flow - drug effects; Pulsatile Flow - physiology; Rats; Rats, Sprague-Dawley; Rodents; Spin Labels; Thoracic Duct - drug effects; Thoracic Duct - metabolism; Thoracic Duct - physiopathology; Vascular Biology and Microcirculation; metabolic syndrome; lymphatic endothelial cells; nitric oxide synthase; lymphatic vessel contraction; lymph flow
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00664.2015

Shear-dependent inhibition of lymphatic thoracic duct (TD) contractility is principally mediated by nitric oxide (NO). Endothelial dysfunction and poor NO bioavailability are hallmarks of vasculature dysfunction in states of insulin resistance and metabolic syndrome (MetSyn). We tested the hypothesis that flow-dependent regulation of lymphatic contractility is impaired under conditions of MetSyn. We utilized a 7-wk high-fructose-fed male Sprague-Dawley rat model of MetSyn and determined the stretch- and flow-dependent contractile responses in an isobaric ex vivo TD preparation. TD diameters were tracked and contractile parameters were determined in response to different transmural pressures, imposed flow, exogenous NO stimulation by S-nitro-N-acetylpenicillamine (SNAP), and inhibition of NO synthase (NOS) by l-nitro-arginine methyl ester (l-NAME) and the reactive oxygen species (ROS) scavenging molecule 4-hydroxy-tempo (tempol). Expression of endothelial NO synthase (eNOS) in TD was determined using Western blot. Approximately 25% of the normal flow-mediated inhibition of contraction frequency was lost in TDs isolated from MetSyn rats despite a comparable SNAP response. Inhibition of NOS with l-NAME abolished the differences in the shear-dependent contraction frequency regulation between control and MetSyn TDs, whereas tempol did not restore the flow responses in MetSyn TDs. We found a significant reduction in eNOS expression in MetSyn TDs suggesting that diminished NO production is partially responsible for impaired flow response. Thus our data provide the first evidence that MetSyn conditions diminish eNOS expression in TD endothelium, thereby affecting the flow-mediated changes in TD lymphatic function.