Blood pressures, heart rate and locomotor activity during salt loading and angiotensin II infusion in protease-activated receptor 2 (PAR2) knockout mice
© McGuire et al; licensee BioMed Central Ltd. 2008
Received: 01 August 2008
Accepted: 21 October 2008
Published: 21 October 2008
In this study we used radiotelemetry to measure hemodynamic variables and locomotor activity in conscious unrestrained male Protease-Activated Receptor 2 (PAR-2) knockout mice in order to provide a detailed assessment of their blood pressure phenotype. In addition we tested for an influence of PAR-2 on salt-sensitivity (8% versus 0.5% NaCl diet, 2.5 weeks) and angiotensin II-induced hypertension (1 μg Ile5-angiotensin II/kg/min versus 0.25 μl/h saline, 2 weeks).
Systolic arterial pressures of PAR-2 -/- (129 ± 1 mmHg, n = 21, P < 0.05) were statistically higher than those of C57BL/6J (124 ± 1 mmHg, n = 33) throughout the 24 h period under baseline conditions. Pulse pressures in PAR-2 -/- were also significantly elevated (33 ± 1 mmHg versus 30 ± 1 mmHg, P < 0.05), whereas diastolic arterial pressures were not. Heart rates in PAR-2 -/- were not significantly different than controls, with the exception that heart rate of PAR-2 -/- was 23 beats per min higher than controls (P < 0.001) during periods of nocturnal activity. The diurnal pattern and intensity of locomotor activity were not found to differ between strains. A high salt diet led to increased blood pressures, decreased heart rates, increased time spent active and decreased intensity levels of locomotor activity. Salt-induced changes in systolic and pulse pressures in PAR-2 -/- were less than in C57B/6J. Angiotensin II treatment increased pressures, decreased heart rates, decreased time spent active and decreased intensity levels of activity of PAR-2 -/-, all to the same extent as C57BL/6J. A trend of lower blood pressures during the middle period of angiotensin II treatment period was observed in individual PAR-2 -/-.
The data indicated gene knockout of PAR-2 was associated with a modest change in blood pressure phenotype. PAR-2 -/- mice exhibited moderate elevation of systolic arterial and pulse pressures, yet no increased diastolic arterial pressure, no increased blood pressure responses to high salt diet and a subtle difference in the time course of the blood pressure responses to angiotensin II infusion.
Protease-activated receptor 2 (PAR2), a 7 transmembrane domain G protein coupled receptor, has been found to be activated endogenously by specific serine proteases [1, 2]. Supposedly, rather than by the binding of any known soluble ligands in the circulation, serine proteases released by endothelial cells and other cells during inflammation and/or injury initiates PAR2-dependent actions that range from endothelial-dependent vasodilation to production of cytokines and stimulated de novo expression of adhesion molecules . No obvious blood pressure phenotypes have been reported in PAR2 -/- albeit such in vivo observations have so far been limited to anaesthetized mice . Studies have reported PAR2 -/- mice were resistant to induction of inflammatory disease models including arthritis [5, 6], colitis , airway inflammation , and vascular acute inflammation [9, 10] and renal inflammation . On the other hand, PAR2 -/- were more susceptible to neurodegenerative inflammation [12, 13] and focal brain ischemia . Still in other studies, PAR2 -/- were no less or more affected than normal mice subjected to endotoxemia  and renal ischemia reperfusion injury . To date there have been no studies in vivo using PAR2 -/- whereby their constitutive hemodynamics have been challenged such as in mouse models of acquired hypertension. High salt diet feeding  and angiotensin II infusions [18, 19] can reveal novel pathophysiological interactions of receptor signaling on hemodynamic control of blood pressure. Serine proteinase activities (renal kallikreins in particular) have been linked to salt-sensitivity [20–22] and both salt- and angiotensin II-induced hypertension have been linked separately to pro-inflammation signalling pathways such as nuclear factor-κB shared in common with PAR2 [23–30]. Such findings provided a good rationale for testing the pathophysiological interactions of PAR2 with regulation of blood pressure during altered hemodynamic states particularly with the development of acquired hypertension.
The goals of this study were to describe the blood pressure phenotype of conscious PAR2 -/- using radiotelemetry. Specifically, we aimed to determine the baseline blood pressure level of PAR2 -/-, and whether PAR2 -/- were more salt-sensitive and/or more responsive to infusion with angiotensin II than controls. These data were expected to inform us about the interaction of PAR2 with blood pressure regulation and provide insight into therapeutic possibilities for PAR2-targetted drugs in the future.
All protocols were approved by the Institutional Animal Care Committee of Memorial University in accordance with the guidelines and principles recommended for the use of animals in research by the Canadian Animal Care Council.
Control mice (PAR2 +/+; C57BL/6J) and PAR2-deficient mice (PAR2 -/-; B6.Cg-F2rl1tm1mslb/J) were purchased from the Jackson Laboratories (Bar Harbor, ME). Except during high-salt (HS) diet feeding, mice were fed a standard regular-salt (RS) feed containing 0.28% sodium (0.5% NaCl), 1% calcium, 0.59% potassium and 0.93% phosphorus (NIH-31 autoclavable open formula mouse diet; Zeigler Bros Inc., PA). High-salt diet containing 8% NaCl was comprised otherwise as above (Zeigler Bros Inc., PA). Mice were provided water ad libitum. Mice were housed individually in air filter-topped cages in a room of the Animal Care Facility of the Health Sciences Center dedicated to recording radiotelemetry data. The room lighting was set to a 12 h light and 12 h dark cycle and room temperature was 20–22°C.
Mice (males; PAR2 +/+: 10–20 weeks of age, 25–30 g; PAR2 -/-: 10–30 weeks of age, 24–30 g) were implanted with a telemeter (TA11PA-C10, Datasciences Inc.) via the right carotid artery [31, 32] under isoflurane/oxygen anaesthesia. All mice were allowed to recover from these surgeries for 13 to 18 days prior to recording their baseline variables. For the HS challenge protocol, the BP data were recorded by telemetry continuously for 3–9 days at baseline and then for 18 days following the switch to experimental diet (5 PAR2 +/+ and 5 PAR2 -/-). For the protocol comparing the effect of high Ang II in each strain, baseline recordings were made for a 4–7 day period. On Day 0 of the Ang II infusion protocol, mice were removed from their rooms shortly after the start of the light period and a micro-osmotic pump (ALZET model 1002) containing either isotonic saline (13 PAR2 +/+ and 7 PAR2 -/-) or Ang II (15 PAR2 +/+ and 9 PAR2 -/-; 1 μg Ile5-angiotensin/kg/min) was implanted dorsally s.c. Pump implantation (~10–15 min) was performed using isoflurane/oxygen anaesthesia, followed by monitoring their recovery for 4–6 h before being returned to their home cages. BP data sampling was then restarted ~18 h later at the start of the next light period (day 1). According to the manufacturer's literature provided with the product, steady state rate of infusion was expected to be reached 12 h after implant of micro-osmotic pumps. BP data in saline-treated and Ang II-treated mice were recorded for 12–13 days before being sacrificed. The proper placement of the catheter tips of telemeters in the aortic arch were confirmed at autopsy.
Hemodynamic (systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR)) and locomotor activity data were sampled for 3 s at 30 s intervals . The 24 h data sets were processed using an Excel spreadsheet application designed for this purpose . Data representing the inactive state for each mouse was defined by locomotor activity signal (Act, in arbitrary units) equal to 0 and active state was defined by Act > 0. Intensity of the continuous activity (Act intensity) was calculated by logarithmic base 10 transformation of all Act values when Act >0. Corrections for calibration drift were applied to data using the external pressure calibrations made at the end of the protocol [17, 32]. Unexpected electrical power failures led to data exclusion and uneven sample sizes on several days of the experiment. Data recorded during cage change days (every 7 days) and day 0 of pump implants have been excluded. Only data sets from mice characterized by a stable 24 h MAP during the baseline recording period and pulse pressure (PP) ≥ 20 mmHg throughout the day were included in analyses. This criterion resulted in exclusion of telemeter data from 1 PAR2 +/+ and 4 PAR2 -/-. Regardless of the PP exclusion criterion, the recordings from these mice typically contained data points at both extremely high and low implausible ranges as well as periods of missing data acquisition signals, which have become characteristics used to identify artifacts in telemetry data.
Values reported and symbols on graphs are the means ± standard error of the mean. For overall characterization of phenotype, the data obtained at baseline preceding both experimental protocols (high salt feeding and micro-osmotic pump implants) were combined for each strain. Linear regression analysis indicated that age did not have an effect on baseline blood pressures or the effects of the experimental protocols in our study. The calculations of difference in telemetry variables during the experimental treatments are paired to the average value of the individual mouse's baseline recordings. There are 6 parts to the presentation of statistical analyses: 1) Comparison of the effect of strain on 12 h light and 12 h dark telemetry variables at baseline (2 way ANOVA). 2) Comparison of the effect of strain on 12 h light and 12 h dark variables at baseline with matching of variables to activity level (Act = 0 or Act >0; 2 way repeated measures ANOVA). 3) Comparison of the effect of strain on change in variables during HS diet (2 way repeated measures ANOVA). 4) Comparison of the effect of treatment (high salt vs normal salt) on variables with time (2 way repeated measures ANOVA). 5) Comparison of the effect of strain on change in variables during micro-osmotic pump treatments (2 way ANOVA). 6) Comparison of the effect of micro-osmotic pump treatment on variables (2 way ANOVA). Bonferroni post-hoc testing was used to identify differences between specific groups in the multiple comparisons. P < 0.05 was considered significant.
Baseline hemodynamics of PAR2 -/- and PAR2 +/+ mice
Summary of baseline hemodynamics of PAR2 -/- and PAR2 +/+ mice.
Ratio PAR2 -/- to PAR2 +/+
12 h dark
131 ± 1
136 ± 1
101 ± 1
102 ± 1
31 ± 1
33 ± 1
HR (beats min-1)
607 ± 6
622 ± 5
12 h light
118 ± 1
122 ± 1
89 ± 1
89 ± 1
29 ± 1
32 ± 1
HR (beats min-1)
587 ± 4
595 ± 5
Activity effects on hemodynamics of PAR2 -/- and PAR2 +/+ mice.
Ratio PAR2 -/- to PAR2 +/+
12 h dark
% time active
52 ± 1
49 ± 2
1.15 ± 0.01
1.17 ± 0.02
SAP inactive (mmHg)
125 ± 1
128 ± 1
SAP active (mmHg)
137 ± 1
142 ± 1
DAP inactive (mmHg)
95 ± 1
96 ± 1
DAP active (mmHg)
106 ± 1
109 ± 1
PP inactive (mmHg)
29 ± 1
33 ± 1
PP active (mmHg)
31 ± 1
34 ± 1
HR inactive (beats min-1)
572 ± 6
581 ± 5
HR active (beats min-1)
640 ± 6
663 ± 6
12 h light
% time active
28 ± 1
26 ± 1
1.01 ± 0.02
0.98 ± 0.02
SAP inactive (mmHg)
112 ± 1
117 ± 1
SAP active (mmHg)
131 ± 1
136 ± 1
DAP inactive (mmHg)
84 ± 1
85 ± 1
DAP active (mmHg)
100 ± 1
102 ± 1
PP inactive (mmHg)
28 ± 1
32 ± 1
PP active (mmHg)
31 ± 1
34 ± 1
HR inactive (beats min-1)
543 ± 4
544 ± 6
HR active (beats min-1)
628 ± 4
634 ± 5
Salt sensitivity of PAR2 -/- versus PAR2 +/+
Angiotensin II effects on hemodynamics of PAR2 -/- and PAR2 +/+
Ang II infusion was associated with similar transient reductions in HR, Act intensity and % time spent active in both strains. We did not observe any effect of micro-osmotic pumps containing saline on the variables of either strain of mouse relative to the baseline period (Figure 4 and Figure 5).
The main findings from our study were that gene knockout of PAR2 was associated with only a modest change in blood pressure phenotype. PAR-2 mice exhibited moderate elevation of systolic arterial and pulse pressures, yet no increase of diastolic arterial pressure, no increased responses to salt and only a subtle difference on the time course of the blood pressure responses to Ang II infusion.
We found small yet significant increases in blood pressures of PAR2 -/- mice which led us to conclude their phenotype is characterized by moderate elevation in systolic arterial and pulse pressures, but not diastolic arterial pressures. Our telemetry data comparisons of PAR2 -/- to the background genetic controls (C57BL/6J) provide the first description of blood pressures and heart rates in conscious PAR2 -/-. Previously it was reported that the acute hemodynamics (i.e. heart rates, blood pressures) of PAR2 -/- were not different than controls based on intracarotid catheter recordings under anaesthesia . Using a radiotelemetry approach for blood pressure phenotyping in conscious unrestrained PAR2 -/- mice, we resolved a very small difference in hemodynamic variables. The magnitude of these differences were so small that the physiological impact may at first glance be considered inconsequential under baseline conditions and further dissection of its nature would appear to be unfeasible. Nevertheless the use of telemetry methodology allows us to conclude with a high degree of confidence that these subtle differences are in fact real effects of PAR2 -/-, being observed consistently in freely behaving conscious mice without the limitations that may be imposed by other methods (e.g. anesthetics, restraint, tail warming). Telemetry has been shown to be the most accurate of current techniques available for assessing BP in rodents and has received recommendation as the gold standard method for quantifying the BP phenotype in experimental animals . We also made use of an advantage of radiotelemetrically acquired data to assess interactions between independent variables in order to explain the overall physiological phenotype. For example, analyses of the radiotelemetry data has the ability to dissect the indirect influence of genotype on hemodynamic variables that may arise as a consequence of behavioural changes occurring in the gene knockout. Locomotor activity changes resulting from an abnormal behaviour (hyperactivity) can result in changes to the distribution pattern of hemodynamic variables because conscious blood pressure in mice has been shown to be strongly influenced by locomotor activity [31, 32]. No other method would likely have identified the small, but significant increase in HR of PAR2 -/- while active at night.
We found that HR in PAR2 -/- were relatively the same as PAR2 +/+ except during activity episodes at night. Differences in HR of PAR2 -/- and PAR2 +/+ during activity of the dark period coincided with similarly raised intensity levels of activity in the dark period (Table 2) which is usual for nocturnal animals. The significance of these findings is unknown, but could reflect a subtle effect of PAR2 -/- on autonomic nervous system reactivity or exercise intolerance.
Slightly higher PP in PAR2 -/- than in PAR2 +/+ could indicate reduced endothelial-derived vasodilator tone, reduced central arterial compliance resulting from morphological and composition changes of blood vessel walls (e.g. increased wall thickness, reduced internal diameters, collagen deposition) and/or increased cardiac stroke volumes in PAR2 -/-. Activation of PAR2 has numerous effects including endothelium-dependent vasodilation [32, 35–38], so an elevated peripheral resistance in knockouts would be consistent with a subtle role played by PAR2 in modulating vascular tone. Endothelial NO synthase (eNOS) is considered a major modulator of peripheral resistance and the 24 h mean blood pressures of eNOS -/- mice were found to increase by ~15% relative to controls when measured by radiotelemetry . The BP elevation observed for PAR2 -/- mice in the present study amounts to approximately one fourth of this level. Such differences in BP may be reduced by compensations from the time of conception so could explain the small size of effect of PAR2 -/- on baseline hemodynamics in mice even if PAR2 was a critical enzyme in blood pressure regulation. Theoretically, the small impact on BP could also underestimate the role played by PAR2 in modulating peripheral resistance (if cardiac output decreased in knockouts as part of compensation) or regulating local blood flow distribution.
For PAR2 to interact pathophysiologically with blood pressure control during high salt diet loading, there should be enzymes that mediate its activation that are linked to blood pressure regulation. The human kallikreins family of serine proteinases consists of several isoforms that have been found to activate PAR2 . It was reported that renal kallikrein activity decreased in salt-sensitive hypertensive animals and renal excretion of kallikreins was increased by angiotensin II [20, 21, 40, 41]. The majority of kallikreins biological actions are mediated through kinins, interaction with thrombin generation and the coagulation-cascade. However, the presence of residual non-kinin effects on blood pressure regulation by renal kallikreins during salt-loading has provided evidence of additional substrates . In the current study we had hypothesized that PAR2 was one such substrate. As a possible contributor to the mechanism of residual blood pressure lowering activity by kallikreins during salt loading, we had expected that PAR2 -/- would have been more salt-sensitive relative to controls, but these mice were in fact less salt sensitive than controls. Even so, the impact of such small absolute differences in the salt-sensitivity of BP between PAR2 -/- and PAR2 +/+ would likely to be physiologically trivial, and suggests that PAR2 is unlikely to play a significant role in the regulation of salt balance. In both strains HR was lowered during HS diet, an observation that has been reported in humans . The data do not exclude PAR2 interaction with non-blood pressure actions of HS diet that remain to be investigated.
In addition to HS diet, a condition where the renin-Ang II system would be downregulated, we also treated mice with Ang II infusion in order to investigate possible interaction with PAR2 on high Ang II acquired hypertension. At the end of 2 weeks, the effects of Ang II on BP were similar in PAR2 -/- and PAR2 +/+ mice. Collating the findings of classic physiology studies in multiple model systems, we expect that the immediate effects of elevating Ang II involve central nervous system and sympathetic nervous system activations and increases in peripheral resistance that are then followed later by mechanisms involving the resetting of kidney function and remodeling of the vasculature. Increasingly often there have been studies that have sought out links between inflammation and hypertension development involving angiotensin II. Studies to induce inflammatory responses in PAR2 -/- have resulted in mixed findings about pathological outcomes and our data support a main finding of a null effect on Ang II-acquired hypertension. Chronic high dose Ang II infusions over the period used in this study were shown to result in production of signs of vascular inflammation and endothelial dysfunction by the end-point, but have not been studied at the early time point (~7 day) at which we observed consistent differences in the trend for hemodynamic changes of PAR2 -/- [18, 19]. We did not rule out the possibility that different results might be obtained in females. While a major interaction between Ang II and PAR2 appears inconsequential to BP in the long term, other pathological effects of high Ang II that arise independent of BP such as endothelial dysfunction or the effects of threshold BP changes by a lower dose of Ang II could be manifested differently in PAR2 -/-. Other characteristics of endothelium-dependent inflammatory responses which have been shown to be different have included the time to onset which was delayed in PAR2 -/-  and both leukocyte adhesion and neointima formation, which were reduced in PAR2 -/-.
In conclusion, PAR2 -/- mice exhibited a BP phenotype which was characterized by modest increases of systolic arterial and pulse pressures. The BP of PAR2 -/- is not more salt-sensitive than that of wild type mice, but differences in the time course of the BP responses to Ang II in PAR2 -/- and PAR2 +/+ may indicate the presence of a subtle influence of PAR2 on Ang II modulation of BP.
This study was funded by operating and infrastructure grants from the Canadian Institutes of Health Research (Regional Partnership Program, ROP 72465; ROP 88065; New Investigator Award, RSH 78370), the Department of Innovation, Trade and Rural Development, Province of Newfoundland (Industrial Research and Innovation Fund, 0405-017; 0506-014; 0708-022; 0708-008) and Canada Foundation for Innovation (New Opportunities Fund, 10027) to JJM.
- Hollenberg MD, Compton SJ: International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev. 2002, 54: 203-217. 10.1124/pr.54.2.203.View ArticlePubMedGoogle Scholar
- Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R: Proteinase-activated receptors. Pharmacol Rev. 2001, 53: 245-282.PubMedGoogle Scholar
- McGuire JJ: Proteinase-activated Receptor 2 (PAR2): a challenging new target for treatment of vascular diseases. Curr Pharm Des. 2004, 10: 2769-2778. 10.2174/1381612043383656.View ArticlePubMedGoogle Scholar
- Damiano BP, Cheung WM, Santulli RJ, Fung-Leung WP, Ngo K, Ye RD, et al: Cardiovascular responses mediated by protease-activated receptor-2 (PAR- 2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. J Pharmacol Exp Ther. 1999, 288: 671-678.PubMedGoogle Scholar
- Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, et al: Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest. 2003, 111: 35-41.PubMed CentralView ArticlePubMedGoogle Scholar
- Kelso EB, Lockhart JC, Hembrough T, Dunning L, Plevin R, Hollenberg MD, et al: Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J Pharmacol Exp Ther. 2006, 316: 1017-1024. 10.1124/jpet.105.093807.View ArticlePubMedGoogle Scholar
- Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, MacNaughton WK, et al: Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol. 2002, 161: 1903-1915.PubMed CentralView ArticlePubMedGoogle Scholar
- Schmidlin F, Amadesi S, Dabbagh K, Lewis DE, Knott P, Bunnett NW, et al: Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol. 2002, 169: 5315-5321.View ArticlePubMedGoogle Scholar
- Lindner JR, Kahn ML, Coughlin SR, Sambrano GR, Schauble E, Bernstein D, et al: Delayed onset of inflammation in protease-activated receptor-2-deficient mice. J Immunol. 2000, 165: 6504-6510.View ArticlePubMedGoogle Scholar
- Tennant GM, Wadsworth RM, Kennedy S: PAR-2 mediates increased inflammatory cell adhesion and neointima formation following vascular injury in the mouse. Atherosclerosis. 2008, 198: 57-64.View ArticlePubMedGoogle Scholar
- Moussa L, Apostolopoulos J, Davenport P, Tchongue J, Tipping PG: Protease-activated receptor-2 augments experimental crescentic glomerulonephritis. Am J Pathol. 2007, 171: 800-808. 10.2353/ajpath.2007.061155.PubMed CentralView ArticlePubMedGoogle Scholar
- Noorbakhsh F, Vergnolle N, McArthur JC, Silva C, Vodjgani M, Andrade-Gordon P, et al: Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. J Immunol. 2005, 174: 7320-7329.View ArticlePubMedGoogle Scholar
- Noorbakhsh F, Tsutsui S, Vergnolle N, Boven LA, Shariat N, Vodjgani M, et al: Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J Exp Med. 2006, 203: 425-435. 10.1084/jem.20052148.PubMed CentralView ArticlePubMedGoogle Scholar
- Jin G, Hayashi T, Kawagoe J, Takizawa T, Nagata T, Nagano I, et al: Deficiency of PAR-2 gene increases acute focal ischemic brain injury. J Cereb Blood Flow Metab. 2005, 25 (3): 302-313. 10.1038/sj.jcbfm.9600021.View ArticlePubMedGoogle Scholar
- Camerer E, Cornelissen I, Kataoka H, Duong DN, Zheng YW, Coughlin SR: Roles of protease-activated receptors in a mouse model of endotoxemia. Blood. 2006, 107: 3912-3921. 10.1182/blood-2005-08-3130.PubMed CentralView ArticlePubMedGoogle Scholar
- Sevastos J, Kennedy SE, Davis DR, Sam M, Peake PW, Charlesworth JA, et al: Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood. 2007, 109: 577-583. 10.1182/blood-2006-03-008870.View ArticlePubMedGoogle Scholar
- Leonard AM, Chafe LL, Montani JP, Van Vliet BN: Increased salt-sensitivity in endothelial nitric oxide synthase-knockout mice. Am J Hypertens. 2006, 19: 1264-1269. 10.1016/j.amjhyper.2006.05.025.View ArticlePubMedGoogle Scholar
- Virdis A, Iglarz M, Neves MF, Amiri F, Touyz RM, Rozen R, et al: Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arterioscler Thromb Vasc Biol. 2003, 23: 1352-1357. 10.1161/01.ATV.0000083297.47245.DA.View ArticlePubMedGoogle Scholar
- De Ciuceis C, Amiri F, Brassard P, Endemann DH, Touyz RM, Schiffrin EL: Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arterioscler Thromb Vasc Biol. 2005, 25: 2106-2113. 10.1161/01.ATV.0000181743.28028.57.View ArticlePubMedGoogle Scholar
- Mills IH, Macfarlane NA, Ward PE, Obika LF: The renal kallikrein-kinin system and the regulation of salt and water excretion. Fed Proc. 1976, 35: 181-188.PubMedGoogle Scholar
- Uehara Y, Hirawa N, Numabe A, Kawabata Y, Ikeda T, Gomi T, et al: Long-term infusion of kallikrein attenuates renal injury in Dahl salt-sensitive rats. Am J Hypertens. 1997, 10: 83S-88S.View ArticlePubMedGoogle Scholar
- Katori M, Majima M: The renal kallikrein-kinin system: its role as a safety valve for excess sodium intake, and its attenuation as a possible etiologic factor in salt-sensitive hypertension. Crit Rev Clin Lab Sci. 2003, 40: 43-115. 10.1080/713609329.View ArticlePubMedGoogle Scholar
- Cleator JH, Zhu WQ, Vaughan DE, Hamm HE: Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood. 2006, 107: 2736-2744. 10.1182/blood-2004-07-2698.PubMed CentralView ArticlePubMedGoogle Scholar
- Lim SY, Tennant GM, Kennedy S, Wainwright CL, Kane KA: Activation of mouse protease-activated receptor-2 induces lymphocyte adhesion and generation of reactive oxygen species. Br J Pharmacol. 2006, 149: 591-599. 10.1038/sj.bjp.0706905.PubMed CentralView ArticlePubMedGoogle Scholar
- Li T, He S: Induction of IL-6 release from human T cells by PAR-1 and PAR-2 agonists. Immunol Cell Biol. 2006, 84: 461-466. 10.1111/j.1440-1711.2006.01456.x.View ArticlePubMedGoogle Scholar
- Fukunaga R, Hirano K, Hirano M, Niiro N, Nishimura J, Maehara Y, et al: Upregulation of proteinase-activated receptors and hypercontractile responses precede development of arterial lesions after balloon injury. Am J Physiol Heart Circ Physiol. 2006, 291: H2388-H2395. 10.1152/ajpheart.01313.2005.View ArticlePubMedGoogle Scholar
- Syeda F, Grosjean J, Houliston RA, Keogh RJ, Carter TD, Paleolog E, et al: Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-kappaB pathways. J Biol Chem. 2006, 281: 11792-11804. 10.1074/jbc.M509292200.View ArticlePubMedGoogle Scholar
- Luo W, Wang Y, Hanck T, Stricker R, Reiser G: Jab1, a novel protease-activated receptor-2 (PAR-2)-interacting protein, is involved in PAR-2-induced activation of activator protein-1. J Biol Chem. 2006, 281: 7927-7936. 10.1074/jbc.M510784200.View ArticlePubMedGoogle Scholar
- Ritchie E, Saka M, Mackenzie C, Drummond R, Wheeler-Jones C, Kanke T, et al: Cytokine upregulation of proteinase-activated-receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase beta in human endothelial cells. Br J Pharmacol. 2007, 150: 1044-1054. 10.1038/sj.bjp.0707150.PubMed CentralView ArticlePubMedGoogle Scholar
- Henke N, Schmidt-Ullrich R, Dechend R, Park JK, Qadri F, Wellner M, et al: Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage. Circ Res. 2007, 101: 268-276. 10.1161/CIRCRESAHA.107.150474.View ArticlePubMedGoogle Scholar
- Van Vliet BN, Chafe LL, Montani JP: Characteristics of 24 h telemetered blood pressure in eNOS-knockout and C57Bl/6J control mice. J Physiol. 2003, 549: 313-325. 10.1113/jphysiol.2003.041897.PubMed CentralView ArticlePubMedGoogle Scholar
- McGuire JJ, Van Vliet BN, Gimenez J, King JC, Halfyard SJ: Persistence of PAR-2 vasodilation despite endothelial dysfunction in BPH/2 hypertensive mice. Pflugers Arch. 2007, 454: 535-543. 10.1007/s00424-007-0226-2.View ArticlePubMedGoogle Scholar
- Van Vliet BN, McGuire JJ, Chafe L, Leonard A, Joshi A, Montani JP: Phenotyping the level of mouse blood pressure by telemetry. Clin Exp Pharmacol Physiol. 2006, 33: 1007-1015. 10.1111/j.1440-1681.2006.04479.x.View ArticlePubMedGoogle Scholar
- Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE: Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood pressure measurement in experimental animals: a statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research. Hypertension. 2005, 45: 299-310. 10.1161/01.HYP.0000150857.39919.cb.View ArticlePubMedGoogle Scholar
- Smeda JS, McGuire JJ: Effects of Poststroke Losartan Versus Captopril Treatment on Myogenic and Endothelial Function in the Cerebrovasculature of SHRsp. Stroke. 2007, 38: 1590-1596. 10.1161/STROKEAHA.106.475087.View ArticlePubMedGoogle Scholar
- McGuire JJ, Hollenberg MD, Bennett BM, Triggle CR: Hyperpolarization of murine small caliber mesenteric arteries by activation of endothelial proteinase-activated receptor 2. Can J Physiol Pharmacol. 2004, 82: 1103-1112. 10.1139/y04-121.View ArticlePubMedGoogle Scholar
- McGuire JJ, Hollenberg MD, Andrade-Gordon P, Triggle CR: Multiple mechanisms of vascular smooth muscle relaxation by the activation of proteinase-activated receptor 2 in mouse mesenteric arterioles. Br J Pharmacol. 2002, 135: 155-169. 10.1038/sj.bjp.0704469.PubMed CentralView ArticlePubMedGoogle Scholar
- McGuire JJ, Dai J, Andrade-Gordon P, Triggle CR, Hollenberg MD: Proteinase-activated receptor-2 (PAR2): vascular effects of a PAR2-derived activating peptide via a receptor different than PAR2. J Pharmacol Exp Ther. 2002, 303: 985-992. 10.1124/jpet.102.040352.View ArticlePubMedGoogle Scholar
- Oikonomopoulou K, Hansen KK, Saifeddine M, Vergnolle N, Tea I, Blaber M, et al: Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs). Biol Chem. 2006, 387: 817-824. 10.1515/BC.2006.104.PubMedGoogle Scholar
- Ardiles LG, Figueroa CD, Mezzano SA: Renal kallikrein-kinin system damage and salt sensitivity: insights from experimental models. Kidney Int Suppl. 2003, S2-S8. 10.1046/j.1523-1755.64.s86.2.x.Google Scholar
- Katori M, Majima M: A missing link between a high salt intake and blood pressure increase. J Pharmacol Sci. 2006, 100: 370-390. 10.1254/jphs.CRJ06003X.View ArticlePubMedGoogle Scholar
- Yosipiv IV, Dipp S, El-Dahr SS: Targeted disruption of the bradykinin B(2) receptor gene in mice alters the ontogeny of the renin-angiotensin system. Am J Physiol Renal Physiol. 2001, 281: F795-F801.View ArticlePubMedGoogle Scholar
- Folkow B, Ely D: Importance of the blood pressure-heart rate relationship. Blood Press. 1998, 7: 133-138. 10.1080/080370598437321.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.