Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II

Zou, Yunzeng; Akazawa, Hiroshi; Qin, Yingjie; Sano, Masanori; Takano, Hiroyuki; Minamino, Tohru; Makita, Noriko; Iwanaga, Koji; Zhu, Weidong; Kudoh, Sumiyo; Toko, Haruhiro; Tamura, Koichi; Kihara, Minoru; Nagai, Toshio; Fukamizu, Akiyoshi; Umemura, Satoshi; Iiri, Taroh; Fujita, Toshiro; Komuro, Issei

doi:10.1038/ncb1137

Cited by 618 publications

(581 citation statements)

References 42 publications

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“…The present work indicates that stretch may activate VEGFR2 through similar mechanism based on the following lines of evidence: (1) the VEGF-neutralizing antibody did not affect stretch-induced VEGFR2 phosphorylation ( Figure 3C); (2) the VEGF-neutralizing antibody failed to block stretch-induced WPB exocytosis and leukocyte adhesion in cultured ECs ( Figure 3E Figure S3); (3) mechanical stretch activated VEGFR2 that was exogenously expressed in 293A cells and its downstream signaling pathways (Supplementary information, Figure S4), similar to the case of the activation of angiotensin II type 1 receptor by stretch [25]. Other components of the mechanical sensor complex and downstream signaling cascades, e.g., stretchactivated cation channels, intergrin signaling and G protein-coupled receptor signaling known to be involved in the mechanotransduction in ECs [9,26], may also play important roles in stretch-induced exocytosis of WPBs, which await further investigations.…”

Section: Discussionmentioning

confidence: 91%

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Xiong

Han

et al. 2013

Cell Res

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Regulated endothelial exocytosis of Weibel-Palade bodies (WPBs), the first stage in leukocyte trafficking, plays a pivotal role in inflammation and injury. Acute mechanical stretch has been closely associated with vascular inflammation, although the precise mechanism is unknown. Here, we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial cells (ECs) through VEGF receptor 2 (VEGFR2) signaling pathways. Stretch triggers a rapid release (within minutes) of von Willebrand factor and interleukin-8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of P-selectin to the cell membrane. We further show that hypertensive stretch significantly induces P-selectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretch-induced endothelial exocytosis is mediated via a VEGFR2/PLCγ1/calcium pathway. Interestingly, stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway. Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments, as well as in acute hypertensive mouse models. These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis, which is modulated by VEGFR2 signaling. Thus, VEGFR2 signaling pathways may represent novel therapeutic targets in limiting hypertensive stretch-related inflammation.

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Section: Discussionmentioning

confidence: 91%

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Xiong

Han

et al. 2013

Cell Res

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“…It is also possible that the AT 1 receptor could be activated without a ligand, for instance by physical changes. There are data showing that the AT 1 receptor in mouse myocytes can be activated by mechanical stretch independent of angiotensin peptides (51). This mechanical activation of the AT 1 receptor is blocked by an AT 1 antagonist, candesartan.…”

Section: Discussionmentioning

confidence: 99%

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Walker

Alexiou

Allen

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (AgtϪ/Ϫ mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in AgtϪ/Ϫ mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in AgtϪ/Ϫ mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both AgtϪ/Ϫ and WT mice during the hour following injection. As well, AgtϪ/Ϫ mice drank appropriate volumes of water following water deprivation for 7 h. However, AgtϪ/Ϫ mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both AgtϪ/Ϫ mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in AgtϪ/Ϫ mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia.

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“…5,8 We have previously reported that pressure overload induces cardiac hypertrophy in angiotensinogen-deficient mice as well as in wild-type (WT) mice and that hypertrophy is significantly attenuated by the inverse agonist, candesartan. 6 Therefore, the inverse agonist activities of ARBs have potential therapeutic benefits, at least in the prevention of load-induced cardiac hypertro-phy. The structural features that are required for the inverse agonist properties of some ARBs have been studied in constitutively active AT 1 receptors that have an Asn 111 mutation.…”

Section: Introductionmentioning

confidence: 99%

“…5 The AT 1 receptor is also activated by the mechanical stress of cellular stretching without the involvement of AngII. 6,7 A ligand capable of suppressing the agonist-independent activities of a receptor is defined as an inverse agonist. 5,8 We have previously reported that pressure overload induces cardiac hypertrophy in angiotensinogen-deficient mice as well as in wild-type (WT) mice and that hypertrophy is significantly attenuated by the inverse agonist, candesartan.…”

Section: Introductionmentioning

confidence: 99%

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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Type 1 angiotensin II (AT 1 ) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT 1 receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT 1 receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT 1 receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT 1 receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT 1 receptor and the stretch-induced activation of AT 1 receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr 113 and between the carboxyl group of olmesartan and Lys 199 and His 256 , were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT 1 -N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor. These results suggest that multivalent interactions between an inverse agonist and the AT 1 receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the Keywords: angiotensin II; cardiac hypertrophy; G protein-coupled receptor; inverse agonist; mechanical stress INTRODUCTIONThe type 1 angiotensin II (AT 1 ) receptor is a member of the G proteincoupled receptor (GPCR) family and mediates most of the actions that angiotensin II (AngII) exerts on the cardiovascular system. 1 AT 1 receptor blockers (ARBs) are non-peptide compounds that selectively bind to the AT 1 receptor and inhibit AngII-induced receptor activation. At present, several ARBs are clinically available as a highly effective and well-tolerated class of drugs for the management of hypertension. In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic proper-

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Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II

Cited by 618 publications

References 42 publications

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

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