Persistence of PAR-2 vasodilation despite endothelial dysfunction in BPH/2 hypertensive mice

McGuire, John J.; Vliet, Bruce N. Van; Giménez, José Carlos Moreno; King, James C.; Halfyard, Sarah J.

doi:10.1007/s00424-007-0226-2

Cited by 24 publications

(43 citation statements)

References 28 publications

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“…However, even under these conditions, PAR2-mediated vasodilation is preserved in mesenteric arteries from SHRSP.ZF [12]. These findings are similar to those from studies using small-caliber (resistance) arteries in other models of cardiovascular and metabolic disease like hypertension [13,14], stroke [15] and type II diabetes [16]. In rats, endothelium-dependent relaxation of vascular smooth muscle in large-conduit arteries, such as the aorta, is mediated mainly by NO, unlike that in small-caliber, resistance-type arteries [17,18].…”

Section: Introductionsupporting

confidence: 76%

Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

Maruyama¹,

Kagota²,

McGuire³

et al. 2015

J Vasc Res

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Endothelium-dependent vasodilation via protease-activated receptor 2 (PAR2) is preserved in mesenteric arteries from SHRSP.Z-Lepr^fa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome even though nitric oxide (NO)-mediated vasodilation is attenuated. Therefore, we examined the PAR2 mechanisms underlying metabolic syndrome-resistant vasodilation in SHRSP.ZF aortas with ageing. In isolated aortas, the PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) caused vasodilation that was sustained in male SHRSP.ZF until 18 weeks of age, but was attenuated afterwards compared with age-matched Wistar-Kyoto rats (controls) at 23 weeks. In contrast, acetylcholine-induced vasodilation was impaired in SHRSP.ZF already at 18 weeks of age. Treatments of aortas with inhibitors of NO synthase and soluble guanylate cyclase abolished the sustained 2fly- and residual acetylcholine-induced vasodilation in SHRSP.ZF at 18 weeks of age. In the aortas of SHRSP.ZF, 8-bromo-cGMP-induced vasodilation, NO production and cGMP accumulation elicited by 2fly were not different from in the controls. PAR2 agonist increased phospho-Ser¹¹⁷⁷-eNOS protein content only in SHRSP.ZF aortas. These results indicate that vasodilation mediated by PAR2 is sustained even though NO-dependent relaxation is attenuated with ageing/exposure to metabolic disorders in large-caliber arteries from SHRSP.ZF. PAR2 stimulation of NO production via an additional pathway that targets phosphorylation of Ser¹¹⁷⁷-eNOS suggests a regulatory mechanism for sustaining agonist-mediated vasodilation in metabolic syndrome.

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Section: Introductionsupporting

confidence: 76%

Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

Maruyama¹,

Kagota²,

McGuire³

et al. 2015

J Vasc Res

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“…The genetically hypertensive BPH/2J (n=24) and normotensive BPN/3J (n=27) male mice used in the present study came from inbred colonies bred at the Alfred Medical Research and Education Precinct Animal Centre (Generation [15][16][17][18][19][20] from breeders purchased at generation 20-36 from Jackson laboratories. The original breeding selection program, took place in the 1970's for at least 23 generations and then brother sister mating followed to create these inbred strains 1 .…”

Section: Supplement Materials and Methods Animalsmentioning

confidence: 99%

“…19 The greater depressor response to enalaprilat was not the only indication of an elevated contribution of the peripheral RAS to BP in the active period. The pattern was accompanied by a greater abundance of Ren1 mRNA in the kidneys of BPH/2J mice during the active period, consistent with a role for kidney-derived renin production in driving the elevated RAS activity.…”

Section: Contribution Of Ras To Hypertension In Bph/2j Micementioning

confidence: 95%

“…9 Although ACE inhibition can influence BP through bradykinin accumulation, this is unlikely to be contributing to the greater depressor response to enalaprilat in BPH/2J mice because the vasodilatory response to bradykinin is reportedly reduced in BPH/2J compared with BPN/3J mice. 19 The greater depressor response to enalaprilat was not the only indication of an elevated contribution of the peripheral RAS to BP in the active period. The pattern was accompanied by a greater abundance of Ren1 mRNA in the kidneys of BPH/2J mice during the active period, consistent with a role for kidney-derived renin production in driving the elevated RAS activity.…”

Section: Contribution Of Ras To Hypertension In Bph/2j Micementioning

confidence: 95%

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A Novel Interaction Between Sympathetic Overactivity and Aberrant Regulation of Renin by miR-181a in BPH/2J Genetically Hypertensive Mice

et al. 2013

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BPH/2J mice are a genetic model of hypertension developed by Schlager 1 by crossing 8 normotensive strains and selecting for elevated blood pressure (BP). Normotensive BPN/3J control mice were bred concurrently by crossing randomly selected mice from the same base population. Recently, the mechanism of the hypertension has been recognized as neurogenic because ganglion blockade abolished the hypertension in BPH/2J mice.2 Furthermore, spectral analysis of BP revealed greater power in the autonomic frequency band, suggesting overactivity of the sympathetic nervous system (SNS), most prominently during the nocturnal active period.2 BPH/2J mice also display exaggerated daynight differences in BP, which are associated with greater neuronal activity in regions of the hypothalamus and amygdala known to be important for cardiovascular regulation. Given the recent success of renal sympathetic nerve ablation for the treatment of resistant hypertension, 3 the importance of renal influences on the expression of neurogenic hypertension has been highlighted. Importantly, the peripheral renin-angiotensin system (RAS) is closely linked to renal sympathetic nerve activity (RSNA) via its ability to stimulate renin secretion, 4 and also through angiotensin II-mediated facilitation of SNA. 5 However, the interaction of the kidney and renal RAS with SNS-mediated hypertension in BPH/2J mice has not been investigated thoroughly. The role of the RAS has been examined in a variety of ways in BPH/2J mice including by measurement of messenger RNA (mRNA) in tissues and various pharmacological assessments. [6][7][8][9][10] Iwao et al 8 reported normal renin activity in plasma, kidney, and submandibular gland of BPH/2J mice, although others found greater renin activity Abstract-Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the reninangiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg IP) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg IP) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2...

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“…[10][11][12][13][14][15][16] Several studies compared PAR2-induced relaxation of vessels in healthy and diseased conditions such as diabetes and metabolic syndrome. [10][11][12][17][18][19] However, knowledge regarding PAR2-induced responses in the vasculature during chronic hypertension is insufficient. This study aimed to investigate whether PAR2-induced relaxation of aortas isolated from chronic hypertensive rats was altered.…”

Section: -4)mentioning

confidence: 99%

Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

Ando

Matsumoto

Kobayashi

et al. 2018

Biological & Pharmaceutical Bulletin

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Hypertension is one of the most prevalent diseases worldwide and can cause harmful complications within the vascular system. Further research on vascular responsiveness to different ligands and diverse receptors in various arteries is required to understand the mechanisms underlying the development of these vascular complications. Here, we investigated the vasorelaxant effect of the protease-activated receptor 2 (PAR2) agonist 2-furoyl-LIGRLO-amide (2-Fly) and two commonest agents, namely endothelium-dependent dilator acetylcholine (ACh) and endothelium-independent dilator sodium nitroprusside (SNP), on the thoracic aorta isolated from aged spontaneously hypertensive rats (SHR) (age, 52 1 weeks). The effects of these agents were compared between aortas isolated from SHR and age-matched normotensive Wistar Kyoto (WKY) rats. Compared with the WKY group, in the SHR group, 2-Fly-induced relaxation was impaired, ACh-induced relaxation was slightly decreased at low concentrations, and SNP-induced relaxation was similar. In addition, 2-Fly-induced aortic relaxation was largely decreased by a PAR2 antagonist (FSLLRY), endothelial denudation, and a nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine (L-NNA) but not by an Akt inhibitor. These results suggested that PAR2-induced relaxations of aortas of aged SHR was impaired, and this impaired aortic relaxation may be attributed to decreased NO bioavailability rather than altered NO sensitivity unrelated to the Akt activity.Key words aorta; endothelium; hypertension; protease-activated receptor 2 (PAR2); relaxation Vascular complications often occur systemically and arise in response to hypertension-associated pathologies, leading to increased mortality and morbidity rates in hypertensive patients worldwide.1) A growing body of evidence suggests that an abnormal vascular tone, for example, augmented contraction and/or restricted relaxation that was induced by various ligands in hypertensive patients and animal models. 2-4)However, completely understanding vascular tone regulation under pathophysiological conditions is highly complex because the action of one ligand on a receptor may evoke different responses among different vessel types. Thus, a better understanding of the association between hypertension and vascular tone, as modulated by receptor activation, will help identify new therapeutic targets for preventing and treating hypertension-associated vascular complications.Protease-activated receptor 2 (PAR2) is a member of the family of protease-activated receptors and is uniquely activated by proteolysis, PAR2 plays important roles in regulating diverse cellular processes during pathophysiological conditions such as atherosclerosis, diabetes, and hypertension. [5][6][7][8][9] In the vascular system, PAR2 activation can modulate the vascular tone. For example, PAR2 activation induced by the PAR2-activating peptide 2-furoyl-LIGRLO-amide (2-Fly) and endothelium-dependent relaxation induced by serine proteases occur by activating the endothelial nitric oxide syntha...

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Persistence of PAR-2 vasodilation despite endothelial dysfunction in BPH/2 hypertensive mice

Cited by 24 publications

References 28 publications

Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

A Novel Interaction Between Sympathetic Overactivity and Aberrant Regulation of Renin by miR-181a in BPH/2J Genetically Hypertensive Mice

Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

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