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  • ARTERY 2014 Abstracts
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No Generation, Blood Pressure and Vascular Stiffness: Lessons from the Angiotensin AT2 Receptor


Vascular remodeling participates in the development and progression of cardiovascular conditions such as hypertension, atherosclerosis or aneurysm. This process is fine-tuned by neuro-humoral regulatory pathways: the renin-angiotensin system (RAS), being one of the most important. Chronic RAS activation, via AT1 receptor (AT1R) stimulation sets on a series of pro-proliferative, pro-fibrotic, pro-inflammatory signals that promote vascular remodeling and lead to adverse cardiovascular outcomes. The prevention of these outcomes after the blockade of this “deleterious” RAS might be at least in part mediated by the activation of the “protective” RAS. The “protective” RAS involves the AT2 receptor (AT2R) with anti-proliferative, anti-fibrotic, anti-inflammatory and antioxidant effects. Some of these protective actions of AT2R stimulation are mediated by AT2R-induced NO generation. Stimulation of AT2R with the new selective, orally active AT2R agonist, Compound 21, in L-NAME hypertensive rats reduced vascular stiffness (pulse wave velocity) and induced vascular structural improvements without lowering blood pressure. These effects cannot be ascribed to NO generation. Alternative effector pathways include activation of protein phosphatases that inactivate the pro-fibrotic MAPKs or anti-apoptotic Bcl-2, down-regulation of MAPKs with NADPH oxidase inhibition and subsequent attenuation of oxidative load, inhibition of NF-κB activity by epoxidation of 11,12-epoxyeicosatrienoic acid, direct and indirect anti-inflammatory action with augmented IL-10 production and T cell differentiation, and, finally, heterodimerization of the AT2R with AT1R that abrogates the AT1R-dependent pro-fibrotic effects.

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Unger, T. No Generation, Blood Pressure and Vascular Stiffness: Lessons from the Angiotensin AT2 Receptor. Artery Res 8, 121 (2014).

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