Characterization of pressure-mediated vascular tone in resistance arteries from bile duct-ligated rats

Ravirajsinh N. Jadeja, Menaka Thounaojam, Sandeep Khurana

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

In cirrhosis, changes in pressure-mediated vascular tone, a key determinant of systemic vascular resistance (SVR), are unknown. To address this gap in knowledge, we assessed ex vivo dynamics of pressurized mesenteric resistance arteries (diameter ~ 260 μm) from bile duct-ligated (BDL) and sham-operated (SHAM) rats and determined the underlying mechanisms. At isobaric intraluminal pressure (70 mmHg) as well as with step-wise increase in pressure (10-110 mmHg), arteries from SHAM-rats constricted more than BDL-rats, and had reduced luminal area. In both groups, incubation with LNAME (a NOS inhibitor) had no effect on pressure-mediated tone, and expression of NOS isoforms were similar. TEA, which enhances Ca2+ influx, augmented arterial tone only in SHAM-rats, with minimal effect in those from BDL-rats that was associated with reduced expression of Ca2+ channel TRPC6. In permeabilized arteries, high-dose Ca2+ and γGTP enhanced the vascular tone, which remained lower in BDL-rats that was associated with reduced ROCK2 and pMLC expression. Further, compared to SHAM-rats, in BDL-rats, arteries had reduced collagen expression which was associated with increased expression and activity of MMP-9. BDL-rats also had increased plasma reactive oxygen species (ROS). In vascular smooth muscle cells in vitro, peroxynitrite enhanced MMP-9 activity and reduced ROCK2 expression. These data provide evidence that in cirrhosis, pressure-mediated tone is reduced in resistance arteries, and suggest that circulating ROS play a role in reducing Ca2+ sensitivity and enhancing elasticity to induce arterial adaptations. These findings provide insights into mechanisms underlying attenuated SVR in cirrhosis.

Original languageEnglish (US)
Pages (from-to)30706-30722
Number of pages17
JournalOncotarget
Volume8
Issue number19
DOIs
StatePublished - Jan 1 2017

Fingerprint

Bile Ducts
Blood Vessels
Arteries
Pressure
Fibrosis
Matrix Metalloproteinases
Vascular Resistance
Reactive Oxygen Species
Peroxynitrous Acid
Mesenteric Arteries
Elasticity
Guanosine Triphosphate
Vascular Smooth Muscle
Smooth Muscle Myocytes
Protein Isoforms
Collagen
salicylhydroxamic acid

Keywords

  • Cirrhosis
  • Mesenteric arteries
  • Myogenic tone
  • Pathology Section
  • Portal hypertension
  • Vascular dysfunction

ASJC Scopus subject areas

  • Oncology

Cite this

Characterization of pressure-mediated vascular tone in resistance arteries from bile duct-ligated rats. / Jadeja, Ravirajsinh N.; Thounaojam, Menaka; Khurana, Sandeep.

In: Oncotarget, Vol. 8, No. 19, 01.01.2017, p. 30706-30722.

Research output: Contribution to journalArticle

Jadeja, Ravirajsinh N. ; Thounaojam, Menaka ; Khurana, Sandeep. / Characterization of pressure-mediated vascular tone in resistance arteries from bile duct-ligated rats. In: Oncotarget. 2017 ; Vol. 8, No. 19. pp. 30706-30722.
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