iNOS expression in vascular resident macrophages contributes to circulatory dysfunction of splanchnic vascular smooth muscle contractions in portal hypertensive rats

Abstract

Portal hypertension, a major complication of cirrhosis, is caused by both increased portal blood flow due to arterial vasodilation and augmented intrahepatic vascular resistance due to sinusoidal constriction. In this study, we examined the possible involvement of resident macrophages in the tone regulation of splanchnic blood vessels using bile duct ligated (BDL) portal hypertensive rats and an in vitro organ culture method. In BDL cirrhosis, the number of ED2-positive resident macrophages increased by two- to fourfold in the vascular walls of the mesenteric artery and extrahepatic portal vein compared with those in sham-operated rats. Many ED1-positive monocytes were also recruited into this area. The expression of inducible nitric oxide (NO) synthase (iNOS) mRNA was increased in the vascular tissues isolated from BDL rats, and accordingly, nitrate/nitrite production was increased. Immunohistochemistry revealed that iNOS was largely expressed in ED1-positive and ED2-positive cells. We further analyzed the effect of iNOS expression on vascular smooth muscle contraction using an in vitro organ culture system. iNOS mRNA expression and nitrate production significantly increased in vascular tissues (without endothelium) incubated with 1 μg/ml lipopolysaccharide (LPS) for 6 h. Immunohistochemistry indicated that iNOS was largely expressed in ED2-positive resident macrophages. α-Adrenergic-stimulated contractility of the mesenteric artery was greatly suppressed by LPS treatment and was restored by N(G)-nitro-L-arginine methyl ester (NO synthase inhibitor); in contrast, portal vein contractility was largely unaffected by LPS. Sodium nitroprusside (NO donor) and 8-bromo-cGMP showed greater contractile inhibition in the mesenteric artery than in the portal vein with decreasing myosin light chain phosphorylation. In the presence of an α-adrenergic agonist, the mesenteric artery cytosolic Ca(2+) level was greatly reduced by sodium nitroprusside; however, the portal vein Ca(2+) level was largely unaffected. These results suggest that the induction of iNOS in monocytes/macrophages contributes to a hypercirculatory state in the cirrhosis model rat in which the imbalance of the responsiveness of visceral vascular walls to NO (mesenteric artery >> portal vein) may account for the increased portal venous flow in portal hypertension.

Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats

“…Moreover, the enhanced VEGF expression by JAK2/STAT3 signalling, though as an angiogenesis promoter, accelerated intestine inflammation [4]. In addition, high iNOS expression also contributed to the hyperdynamic splanchnic circulation in portal hypertension by regulating splanchnic vascular smooth muscle contractions [34].…”

Upregulation of Inducible Nitric Oxide Synthase Contributes to Attenuated Cutaneous Vasodilation in Essential Hypertensive Humans

“…However, the initial stimulus (or stimuli) that increase(s) iNOS in hypertensive cutaneous microvasculature remain unclear. Possible candidates include a host of immune modulators including tumor necrosis factor α (TNFα), IL-6, COX-2, and elevated angiotensin II 40 . As such, potential pharmacological targets for the treatment of hypertension-induced microvascular dysfunction include the angiotensin pathway and novel anti-inflammatory compounds such as acromalin which decreases iNOS and COX-2 expression by altering TNFα and IL-6 41 .…”

Glutamine prevents oxidative stress in a model of portal hypertension

“…Kajita et al[33] observed that iNOS expression in vascular resident macrophages contributed to the circulatory dysfunction of splanchnic vascular smooth muscle contractions in PH rats[33]. Xu et al[34], in a study with male Sprague-Dawley rats submitted to intra-hepatic PH induced by the injection of CCl 4 , noted that iNOS contributes to the haemodynamic alterations of PH secondary to increased levels of NO[34].…”