Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats

Ribera, Jordi; Pauta, Montse; Melgar-Lesmes, Pedro; Tugues, Sònia; Fernández‐Varo, Guillermo; Held, Kara F.; Sòria, Guadalupe; Tudela, Raúl; Planas, Anna M.; Fernández‐Hernando, Carlos; Arroyo, Vicente; Jiménez, Wladimiro; Morales-Ruíz, Manuel

doi:10.1136/gutjnl-2011-300703

Cited by 50 publications

(50 citation statements)

References 31 publications

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“…For example, mesenteric lymphatic vessels in cirrhotic rats were found to have increased endothelial cell eNOS expression and decreased smooth muscle cell coverage [63]; this diminished smooth muscle cell coverage was reversed by inhibition of eNOS. These and other data emphasise the importance of the lymphatic vascular system in liver diseases [64].…”

Section: Mesenteric Vascular Pathophysiologymentioning

confidence: 99%

Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

Iwakiri

Shah

Rockey

2014

Journal of Hepatology

258

233

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Summary Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system’s cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm’s law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the liver, as well as those in the mesenteric vascular circulation. Translational implications of recent research and the future directions that it points to are also highlighted.

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Section: Mesenteric Vascular Pathophysiologymentioning

confidence: 99%

Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

Iwakiri

Shah

Rockey

2014

Journal of Hepatology

258

233

View full text Add to dashboard Cite

show abstract

“…Increased levels of eNOS and NO were observed in endothelial cells isolated from mesenteric lymphatic vessels of cirrhotic rats, which was also attributed to decreased smooth muscle cell coverage of mesenteric lymphatic vessels in those rats [131]. Excessive NO-mediated relaxation of mesenteric lymphatic vessels may have implications in the formation of ascites (fluid accumulation in the peritoneal cavity), which is commonly associated with cirrhosis with portal hypertension [132].…”

Section: No and Liver Diseasesmentioning

confidence: 99%

Nitric oxide in liver diseases

Iwakiri

Kim

2015

Trends in Pharmacological Sciences

226

177

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Nitric oxide (NO) and its derivatives play important roles in the physiology and pathophysiology of the liver. Despite its diverse and complicated roles, certain patterns of the effect of NO on the pathogenesis and progression of liver diseases are observed. In general, NO derived from endothelial NO synthase (eNOS) in liver sinusoidal endothelial cells (LSECs) is protective against disease development, while inducible NOS (iNOS)-derived NO contributes to pathological processes. This review addresses the roles of NO in the development of various liver diseases with a focus on recently published articles. We present here two recent advances in understanding NO-mediated signaling, nitrated fatty acids and S-guanylation, and conclude with suggestions on future directions of NO-related studies on the liver.

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“…To validate the sensitivity of our measurements to changes in lymphatic function, we used a dermal nitric oxide (NO) donor ointment. NO has been shown to be a regulator of lymphatic function in several pathophysiological or inflammatory conditions (1,31,35,39,58). Additionally, NO has been implicated in the inhibition of the intrinsic contractile capabilities of isolated lymphatic vessels (20,47) and the slowing of lymph transport in vivo (61,73).…”

mentioning

confidence: 99%

Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging

Nelson

Akin

Weiler

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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The ability to quantify collecting vessel function in a minimally invasive fashion is crucial to the study of lymphatic physiology and the role of lymphatic pump function in disease progression. Therefore, we developed a highly sensitive, minimally invasive research platform for quantifying the pumping capacity of collecting lymphatic vessels in the rodent tail and forelimb. To achieve this, we have integrated a near-infrared lymphatic imaging system with a feedback-controlled pressure cuff to modulate lymph flow. After occluding lymphatic flow by inflating a pressure cuff on the limb or tail, we gradually deflate the cuff while imaging flow restoration proximal to the cuff. Using prescribed pressure applications and automated image processing of fluorescence intensity levels in the vessels, we were able to noninvasively quantify the effective pumping pressure (P(eff), pressure at which flow is restored after occlusion) and vessel emptying rate (rate of fluorescence clearance during flow occlusion) of lymphatics in the rat. To demonstrate the sensitivity of this system to changes in lymphatic function, a nitric oxide (NO) donor cream, glyceryl trinitrate ointment (GTNO), was applied to the tails. GTNO decreased P(eff) of the vessels by nearly 50% and the average emptying rate by more than 60%. We also demonstrate the suitability of this approach for acquiring measurements on the rat forelimb. Thus, this novel research platform provides the first minimally invasive measurements of P(eff) and emptying rate in rodents. This experimental platform holds strong potential for future in vivo studies that seek to evaluate changes in lymphatic health and disease.

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Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats

Abstract: The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.

Cited by 50 publications

References 31 publications

Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

Nitric oxide in liver diseases

Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging

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