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Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats.

ABSTRACT: The role of angiotensin II type 2 receptors (AT2Rs) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats, AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. Because FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old-rat resistance arteries. Mesenteric resistance arteries (250 mum in diameter) were isolated from old (24 months) and control (4 months) rats receiving hydralazine (16 mg/kg per day; 2 weeks) or water. FMD, NO-mediated dilation, and endothelial NO synthase expression were lower in old versus control rats. AT2R blockade improved FMD in old rats, suggesting that AT2R stimulation produced vasoconstriction. AT2R expression was higher in old rats and mainly located in the smooth muscle layer. In old rats, AT2R stimulation induced endothelium-independent contraction, which was suppressed by the antioxidant Tempol. Reactive oxygen species level was higher in old-rat arteries than in controls. Hydralazine improved FMD and NO-dependent dilation in old rats without change in AT2R expression and location. In old rats treated with hydralazine, reactive oxygen species level was reduced in endothelial and smooth muscle cells, and AT2R-dependent contraction was abolished. Thus, AT2R stimulation induced vasoconstriction through activation of reactive oxygen species production, contributing to decrease FMD in old-rat resistance arteries. Hydralazine suppressed AT2R-dependent reactive oxygen species production and AT2R-dependent contraction, improving FMD. Importantly, endothelial alterations in aging were reversible. These findings are important to consider in the choice of vasoactive drugs in aging.

SUBMITTER: Pinaud F

PROVIDER: S-EPMC2231526 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats.

Pinaud Frederic F Bocquet Arnaud A Dumont Odile O Retailleau Kevin K Baufreton Christophe C Andriantsitohaina Ramaroson R Loufrani Laurent L Henrion Daniel D

Hypertension (Dallas, Tex. : 1979) 20070507 1

The role of angiotensin II type 2 receptors (AT2Rs) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats, AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. Because FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old-rat resistance arteries. Mesenteric ...[more]

PMID: 17485601

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Project description:Background/Aim:The proliferation and migration of lymphatic endothelial cells (LECs) is essential for lymphatic vessel growth (also known as lymphangiogenesis), which plays a crucial role in regulating the tissue fluid balance and immune cell trafficking under physiological and pathological conditions. Several growth factors, such as VEGF-C, can stimulate lymphangiogenesis. However, the effects of angiotensin II (Ang II) on the proliferation and migration of mouse LECs and the underlying potential mechanisms remain unknown. Methods:Wild-type mice were infused with Ang II (1,000 ng/kg/min) for 1-2 weeks. Murine LECs were stimulated with Ang II (500 nM) or saline for 12-48 h. Cell proliferation was determined with 5-bromo-2-deoxyuridine (BrdU) incorporation assays, while cell migration was assessed by scratch wound healing and transwell chamber assays. The gene expression profiles were obtained by time series microarray and real-time PCR analyses. Results:Ang II treatment significantly induced lymphangiogenesis in the hearts of mice and the proliferation and migration of cultured LECs in a time-dependent manner. This effect was completely blocked by losartan, an angiotensin II type 1 receptor (AT1R) antagonist. The microarray results identified 1,385 differentially expressed genes (DEGs) at one or more time points in the Ang II-treated cells compared with the control saline-treated cells. These DEGs were primarily involved in biological processes and pathways, including sensory perception of smell, the G protein coupled receptor signaling pathway, cell adhesion, olfactory transduction, Jak-STAT, alcoholism, RIG-I-like receptor and ECM-receptor interaction. Furthermore, these DEGs were classified into 16 clusters, 7 of which (Nos. 13, 2, 8, 15, 7, 3, and 12, containing 586 genes) were statistically significant. Importantly, the Ang II-induced alterations the expression of lymphangiogenesis-related genes were reversed by losartan. Conclusion:The results of the present indicate that Ang II can directly regulate the proliferation and migration of LECs through AT1R in vivo and in vitro, which may provide new potential treatments for Ang II-induced hypertension and cardiac remodeling.

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Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats.

Publications

Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats.

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