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.
Highlights
Cirrhosis is characterized by contrasting changes in intrahepatic and extra-hepatic vascular beds―intrahepatic vascular resistance increases while systemic vascular resistance (SVR) decreases [1, 2]
We demonstrated previously that the small mesenteric arteries from rats, in isobaric conditions, develop stable vasoconstriction known as myogenic tone (MT), and with step-wise increase in intraluminal pressure, constrict, a phenomenon known as myogenic response (MR) [12, 13]
The mesenteric arteries isolated from bile duct-ligated (BDL)- and SHAM-rats were pressurized at 70 mmHg and allowed to develop spontaneous constriction
Summary
Cirrhosis is characterized by contrasting changes in intrahepatic and extra-hepatic vascular beds―intrahepatic vascular resistance increases while systemic vascular resistance (SVR) decreases [1, 2]. These hemodynamic changes lead to portal hypertension (PHT), and arterial hypotension, respectively. Increased intrahepatic vascular resistance contributes to development of complications such as gastro-esophageal varices and ascites, and at the same time, attenuated SVR reduces renal perfusion that promotes fluid retention, and impedes our ability to treat those complications. In patients with cirrhosis, arterial hypotension and reduced SVR are critical barriers to pharmacological approaches to reduce intrahepatic vascular resistance and treat PHT
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