Oncotarget

Research Papers: Pathology:

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

Ravirajsinh N. Jadeja, Menaka C. Thounaojam and Sandeep Khurana _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:30706-30722. https://doi.org/10.18632/oncotarget.15409

Metrics: PDF 640 views  |   HTML 1905 views  |   ?  


Abstract

Ravirajsinh N. Jadeja1, Menaka C. Thounaojam2 and Sandeep Khurana1

1 Digestive Health Center, Medical College of Georgia, Augusta, GA, USA

2 Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA

Correspondence to:

Sandeep Khurana, email:

Keywords: cirrhosis, portal hypertension, myogenic tone, vascular dysfunction, mesenteric arteries, Pathology Section

Received: August 19, 2016 Accepted: February 01, 2017 Published: February 16, 2017

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 15409