Vascular dysfunction and fibrosis in stroke-prone spontaneously hypertensive
rats: The aldosterone-mineralocorticoid receptor-Nox1 axis
#MMPMID28478264
Harvey AP
; Montezano AC
; Hood KY
; Lopes RA
; Rios F
; Ceravolo G
; Graham D
; Touyz RM
Life Sci
2017[Jun]; 179
(?): 110-119
PMID28478264
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AIMS: We questioned whether aldosterone and oxidative stress play a role in
vascular damage in severe hypertension and investigated the role of Nox1 in this
process. MATERIALS AND METHODS: We studied mesenteric arteries, aortas and
vascular smooth muscle cells (VSMC) from WKY and SHRSP rats. Vascular effects of
eplerenone or canrenoic acid (CA) (mineralocorticoid receptor (MR) blockers),
ML171 (Nox1 inhibitor) and EHT1864 (Rac1/2 inhibitor) were assessed.
Nox1-knockout mice were also studied. Vessels and VSMCs were probed for Noxs,
reactive oxygen species (ROS) and pro-fibrotic/inflammatory signaling. KEY
FINDINGS: Blood pressure and plasma levels of aldosterone and galectin-3 were
increased in SHRSP versus WKY. Acetylcholine-induced vasorelaxation was decreased
(61% vs 115%) and phenylephrine-induced contraction increased in SHRSP versus WKY
(E(max) 132.8% vs 96.9%, p<0.05). Eplerenone, ML171 and EHT1864 attenuated
hypercontractility in SHRSP. Vascular expression of collagen, fibronectin, TGF?,
MCP-1, RANTES, MMP2, MMP9 and p66Shc was increased in SHRSP versus WKY. These
changes were associated with increased ROS generation, 3-nitrotyrosine expression
and Nox1 upregulation. Activation of vascular p66Shc and increased expression of
Nox1 and collagen I were prevented by CA in SHRSP. Nox1 expression was increased
in aldosterone-stimulated WKY VSMCs, an effect that was amplified in SHRSP VSMCs
(5.2vs9.9 fold-increase). ML171 prevented aldosterone-induced VSMC Nox1-ROS
production. Aldosterone increased vascular expression of fibronectin and PAI-1 in
wild-type mice but not in Nox1-knockout mice. SIGNIFICANCE: Our findings suggest
that aldosterone, which is increased in SHRSP, induces vascular damage through
MR-Nox1-p66Shc-mediated processes that modulate pro-fibrotic and pro-inflammatory
signaling pathways.
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