Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

Abstract

Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased ( À90%) or increased ( þ 100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10 ± 1 Â 10 3 to 17 ± 2 Â 10 3 lm 2 ; 6 weeks: 13 ± 2 Â 10 3 to 24 ± 3 Â 10 3 lm 2 ). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (Ø: 385 ± 13 to 463±14 lm). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 Â 10 3 ±1 Â 10 3 lm 2 ). The diameter of the HF arteries of normotensive rats increased (Ø: 463 ± 22 lm) but no expansion occurred in the HF arteries of hypertensive rats (Ø: 471 ± 16 lm). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (Ø: 419 ± 13 to 475±16 lm). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean Ø between 235 and 290 lm), and infiltration of monocyte/macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition.

Cyclooxygenase-2-derived prostanoids reduce inward arterial remodeling induced by blood flow reduction in old obese Zucker rat mesenteric arteries

“…Thus, it is considered a good animal model to study the metabolic syndrome (Kurtz et al, 1989). In OZR, mesenteric arteries were submitted to a chronic decrease in blood flow, which has been previously shown to induce inward remodeling (Buus et al, 2001;Lemkens et al, 2012;Loufrani et al, 2002a;Pourageaud and De Mey, 1997;van den Akker et al, 2011). Inward remodeling is due to reduced endothelium stimulation leaving unbalanced local vasoconstrictor tone (Bakker et al, 2008;Baron-Menguy et al, 2010).…”

Endothelin

“…SOL1 has been described as a dual ECE/NEP nonpeptide inhibitor, although it is less effective at inhibiting ECE-1 compared with NEP at neutral pH in vitro. However, the compound was effective in inhibiting the Big-ET-1-induced rise in blood pressure in DOCA salt hypertensive rats (10 μ mol⋅kg −1 ) ( Nelissen et al, 2012 ) and chronic treatment reduced macrophage infiltration ( Lemkens et al, 2012a ). SOL1 normalized impaired endothelium-derived hyperpolarizing factor responses in spontaneously hypertensive rats, although there was no effect on blood pressure ( Lemkens et al, 2012b ).…”

Macrophage depletion lowers blood pressure and restores sympathetic nerve α2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

“…Vascular macrophage infiltration may be somewhat specific for the splanchnic circulation as we found macrophages in MAs but not in skeletal muscle arteries. Macrophage infiltration into the wall of mesenteric resistance arteries is a common finding in DOCA-salt and ANG II-induced systemic hypertension (11,31,36). Macrophage infiltration into the wall of the pulmonary artery also occurs in animal models of pulmonary hypertension (45).…”