Abstract
Background and AimA neuronal pathway participates in the development of portal hypertension: blockade of afferent sensory nerves in portal vein ligated (PVL) rats simultaneously prevents brain cardiovascular regularory nuclei activation, neuromodulator overexpression in superior mesenteric ganglia, sympathetic atrophy of mesenteric innervation and hemodynamic alterations. Here we investigated in PVL rats alterations in neuromodulators and signaling pathways leading to axonal regression or apoptosis in the superior mesenteric ganglia and tested the effects of the stimulation of neuronal proliferation/survival by using a tyrosine kinase receptor A agonist, gambogic amide.ResultsThe neuronal pathway was confirmed by an increased neuronal afferent activity at the vagal nodose ganglia and the presence of semaphorin3A in sympathetic pre-ganglionic neurons at the intermediolateral nucleus of the spinal cord of PVL rats. Expression of the active form of tyrosine kinase receptor A (phosphorylated), leading to proliferation and survival signaling, showed a significant reduction in PVL comparing to sham rats. In contrast, the apoptotic and axonal retraction pathways were stimulated in PVL, demonstrated by a significant overexpression of semaphorin 3A and its receptor neuropilin1, together with increases of cleaved caspase7, inactive poly(ADP-ribose) polymerase and Rho kinase expression. Finally, the administration of gambogic amide in PVL rats showed an amelioration of hemodynamic alterations and sympathetic atrophy, through the activation of survival pathways together with the inhibition of apoptotic cascades and Rho kinase mediated axonal regression.ConclusionThe adrenergic alteration and sympathetic atrophy in mesenteric vessels during portal hypertension is caused by alterations on neuromodulation leading to post-ganglionic sympathetic regression and apoptosis and contributing to splanchnic vasodilation.
Highlights
The hemodynamic alteration of portal hypertension in patients with liver cirrhosis contributes to most of the clinical manifestations of the disease: gastrointestinal bleeding, hepatic encephalopathy, ascites and renal failure
By analyzing the superior mesenteric ganglion (SMG) of portal vein ligated (PVL) rats, we have shown an overexpression of nerve growth factor (NGF) and its precursor, as well as an increase in the neurotrophin receptor p75 (p75NTR) and in the chemorepellent molecule semaphorine 3A (Sema3A) [6]
This study was aimed to (i) confirm the implication of the neuronal pathway in portal hypertension by analyzing two intermediate structures: the nodose ganglia in the afferent direction, containing the neuronal soma of afferent sensitive nerves running along the vagus nerve and the intermediolateral nucleus of the spinal cord in the efferent direction, containing the neuronal bodies of pre-ganglionic sympathetic nerves; (ii) further explore the neuromodulators and signaling pathways that, in the SMG of PVL rats, lead to Sema3A/ProNGF/p75NTR-mediated axonal regression or apoptosis; and (iii) find out whether treatment of PVL rats with gambogic amide, a tyrosine kinase receptor A (TrkA) agonist, inhibits this neurodegenerative pathway, and the hemodynamic alteration and sympathetic atrophy of portal hypertension disappear or improve
Summary
The hemodynamic alteration of portal hypertension in patients with liver cirrhosis contributes to most of the clinical manifestations of the disease: gastrointestinal bleeding, hepatic encephalopathy, ascites and renal failure. By analyzing the SMG of portal vein ligated (PVL) rats, we have shown an overexpression of nerve growth factor (NGF) and its precursor (proNGF), as well as an increase in the neurotrophin receptor p75 (p75NTR) and in the chemorepellent molecule semaphorine 3A (Sema3A) [6] This altered neuromodulator expression in the SMG of PVL rats suggested that the adrenergic downregulation and sympathetic atrophy observed in mesenteric vessels might have their origin in disorders leading to axonal regression and/or apoptosis. A neuronal pathway participates in the development of portal hypertension: blockade of afferent sensory nerves in portal vein ligated (PVL) rats simultaneously prevents brain cardiovascular regularory nuclei activation, neuromodulator overexpression in superior mesenteric ganglia, sympathetic atrophy of mesenteric innervation and hemodynamic alterations. We investigated in PVL rats alterations in neuromodulators and signaling pathways leading to axonal regression or apoptosis in the superior mesenteric ganglia and tested the effects of the stimulation of neuronal proliferation/survival by using a tyrosine kinase receptor A agonist, gambogic amide
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