Published online before print April 9, 2007, doi: 10.1161/HYPERTENSIONAHA.106.085589
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2007;49:1321.)
© 2007 American Heart Association, Inc.
Original Articles |
Junctional Adhesion Molecule-1 Is Upregulated in Spontaneously Hypertensive Rats
Evidence for a Prohypertensive Role Within the Brain Stem
From the Department of Physiology, Bristol Heart Institute, School of Medical Sciences (H.W., B.L., S.K., J.F.R.P.), and Henry Wellcome Laboratories for Integrated Neuroscience and Endocrinology (D.M.), University of Bristol, Bristol, United Kingdom; and the Department of Physiology (M.M.) and Experimental Animal Center (K.K.), Fukushima Medical University School of Medicine, Fukushima, Japan
Correspondence to Hidefumi Waki, Department of Physiology, Bristol Heart Institute, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom. E-mail h-waki{at}wakayama-med.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Junctional adhesion molecule-1 (JAM-1) forms part of the tight junction between adjacent endothelial cells. Using microarray technology, we showed previously that JAM-1 was differentially expressed in the brain stem of spontaneously hypertensive rats compared with normotensive Wistar–Kyoto (WKY) rats. In this study, we quantified the expression of JAM-1 in the brain stem of spontaneously hypertensive rats and WKY rats and established whether any differential expression was confined to this region of the brain or was ubiquitous throughout the central nervous system and, indeed, the whole body. Because the nucleus tractus solitarii plays a pivotal role in arterial pressure regulation, we assessed whether JAM-1 in this region affects the chronic regulation of arterial pressure. Real time RT-PCR revealed that JAM-1 mRNA was upregulated in multiple regions of the brain and all of the peripheral vascular beds studied. In the nucleus tractus solitarii, the level of JAM-1 mRNA was significantly higher in both young (3-week–old, prehypertensive) and adult male spontaneously hypertensive rats (15 to 18 weeks old) than that of age-matched WKY rats (fold differences; prehypertensives: 1.01±0.06 versus 1.59±0.13; n=10; P<0.01; adult: 1.08±0.14 versus 2.86±0.57; n=10; P<0.01). After adenoviral-mediated expression of JAM-1 in the nucleus tractus solitarii of adult WKY rats (15 weeks old; n=6), systolic pressure was increased from 120±4 to 132±4 mm Hg (P<0.01). Our data suggest that JAM-1 expression in the spontaneously hypertensive rat is upregulated throughout the body compared with the WKY rat and that this is not secondary to the hypertension. When JAM-1 is expressed in the nucleus tractus solitarii, it raises arterial pressure, suggesting a novel prohypertensive role for this protein within the brain stem.
Key Words: hypertension • brain stem • inflammation • baroreflex control • adhesion molecules
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Essential hypertension is a complex polygenic trait with underlying genetic components, many of which remain unknown. Unmasking these genes may provide novel information about blood regulation and could be potential future targets for therapeutic intervention. This is pertinent, because
50% of patients with hypertension on antihypertensive medication continue to have elevated levels of blood pressure (www.heartstats.org).1 Despite accumulating evidence that gene expression profiles are altered in essential hypertension,2,3 prohypertensive genes remain unclear. One confounding factor is that hypertension itself induces changes in gene expression as a secondary effect. We are exploring the role of the autonomic nervous system in the etiology of hypertension. It is documented that human essential hypertension is associated with a high level of sympathetic nerve activity in humans.4–6 Grassi6 postulated that neurogenic hypertension is maintained by sympathetic overactivity and that this may even be causative. Consistent with that viewpoint, Smith et al5 have shown sympathetic overactivity in white coat hypertensive subjects. Furthermore, in a rat model of hypertension (the spontaneously hypertensive rat [SHR]), sympathetic nerve activity is also substantially elevated relative to Wistar–Kyoto (WKY) rats.7,8 It thus appears that the sympathetic nervous system may play a key role in the manifestation of hypertension in both humans and animal models. Although numerous brain stem regions can control sympathetic nerve activity, the nucleus of the solitary tract (NTS) is one of the key central regions playing a role in the regulation of both the set point of arterial pressure,9–11 as well as baroreflex gain control, a feedback mechanism essential for homeostatic regulation of arterial pressure.10,12,13 A preliminary cDNA microarray experiment14 suggested several differentially expressed genes in the NTS between SHR and their progenitor strain, the WKY rat. One of them was junctional adhesion molecule (JAM)-1. This gene was upregulated in both adult and juvenile (prehypertensive) SHRs and, hence, not secondary to the high blood pressure. JAM-1 is a member of the immunoglobulin superfamily of adhesion molecules that form tight junctions between adjacent endothelial cells and, therefore, form a part of the blood–brain barrier.15,16 JAM-1 has other functions, such as promotion of leukocyte-endothelial adhesion and subsequent inflammation.17 This might be important, because leukocyte accumulation within the systemic circulation was deemed to be a contributing factor for the hypertension in the SHR because of enhanced hemodynamic resistance.18 In addition, JAM-1 is also a risk factor for both atherosclerosis and atherothrombosis,17,19 both of which can be related to hypertension.20
In this study, we have quantified the level of JAM-1 gene expression in the brain stem of SHR relative to WKY rats using real-time RT-PCR and assessed JAM-1 expression in other regions of the brain, as well as numerous peripheral tissues. Our findings indicate that, in the SHR brain (including NTS), expression of JAM-1 mRNA is increased and shifted toward a transcript containing an extended 3' untranslated region (3'UTR); this effectively leads to higher levels of immunoreactive JAM-1 protein. Importantly, chronic overexpression of JAM-1 in the NTS of WKY rats using viral gene transfer raised arterial pressure supporting a novel prohypertensive role for this protein.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Procedures were carried out according to the United Kingdom Home Office Guidelines on Animals (Scientific Procedures) Act of 1986. The animals were housed individually, allowed normal rat chow and drinking water ad libitum, and kept on a 12-hour light/12-hour dark cycle.
Differential Gene Expression in the SHR and WKY Rats
Extraction of RNA
Both 3- (SHR, n=10; WKY, n=10) and 15- to 18-week–old (SHR, n=10; WKY, n=10) male rats were humanely killed by cervical dislocation. Regions of the brain (cerebellum, cerebral cortex, NTS, paraventricular nuclei, rostral ventrolateral medulla, and supraoptic nuclei) and internal organs (eg, liver, lung, kidney, spleen, skeletal muscle, and heart) were dissected (or punched if brain) rapidly from each animal and homogenized in 400 µL of TRIzol reagent (Invitrogen). To avoid contamination with genomic DNA, the RNA samples were treated with RNase-free DNase I (Roche Diagnostics GmbH). RNA purity was verified by performing PCR on samples not treated with reverse transcriptase.
Quantitative RT-PCR
ß-Actin, JAM-1, JAM-3, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 genes were tested in this study; primer details are available in an online data supplement at http://hyper.ahajournals.org. For JAM-1, 2 different sets of primers were used (for the coding part of the transcript, nucleotides 430 to 652 or nucleotides 1145 to 1385 for the 3'UTR, the numbers refer to the GeneBank entry BC065309) to determine potential variation in splicing between SHR and WKY. Real-time RT-PCRs were carried out using a DNA Engine Opticon 2 system (MJ Research) and the QuantiTect SYBR Green RT-PCR kit (Qiagen), as described recently.11 Expression of target genes was assessed in relation to a housekeeping gene (ß-actin) using the comparative (2–
CT) method21 in each sample. Fold differences against average values of WKY were calculated.
Immunohistochemistry for JAM-1 in the Brain Stem
Methods for JAM-1 immunohistochemistry are detailed in the data supplement.
Telemetric Recording of Arterial Pressure
Male rats (WKY, 15 weeks old; n=12) were anesthetized with ketamine (60 mg/kg) and medetomidine (250 µg/kg) intramuscularly. A radio transmitter (Data Sciences International; TA11PA-C40) was implanted to record arterial pressure from the abdominal aorta as described previously.22 Anesthesia was reversed with atipamezole (1 mg/kg). Transmitter implantation occurred 7 to 10 days before the first control arterial pressure readings were obtained.
In Vivo Gene Transfer into NTS
Ad-CMV-JAM-1 (3.24x1010 pfu/mL), a replication-deficient recombinant adenoviral vector, driving the expression of JAM-1 under control of the human cytomegalovirus (CMV) promoter was constructed using standard methods of homologous recombination from IMAGE5599898 clone. As a control, Ad-CMV-eGFP (3.20x1010 pfu/mL) expressing enhanced green fluorescent protein (eGFP) was used. After control readings, animals were reanesthetized. Four 100-nL bilateral microinjections of viral suspension (either Ad-CMV-JAM-1 or Ad-CMV-eGFP) were made into the NTS at separate sites spanning ±500 µm rostral/caudal to the calamus scriptorius, 350 to 600 µm from midline, and 500 to 600 µm below the dorsal surface of the medulla. Each injection was made over 1 minute. To avoid postsurgical cardiovascular effects, animals were allowed to recover for 5 days before blood pressure data were sampled. Data analysis was performed using the Hey-Presto system23 on the day before NTS microinjection of virus and on days 5 to 7 and 14 after microinjections. On these days, arterial pressure was measured continuously for 5 minutes every hour from 9:00 AM until 8:05 AM on the following day. Heart rate (HR) was derived from the interpulse interval. Averaged systolic blood pressure (SBP) and HR were calculated. The spontaneous cardiac baroreflex gain (sBRG) was also determined from spontaneous changes in SBP and HR as described previously.22,23
Data Analysis
Group data were expressed as mean±SEM. To evaluate time-dependent effects of JAM-1 expression, we used 2-way repeated-measures ANOVA and the Scheffe test for multiple comparisons of cardiovascular variables across time and between different groups. A paired/unpaired t test was also used for comparisons between 2 groups. Differences were considered significant if P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Quantitative Comparison of JAM-1 Gene Expression in WKY Rats and SHRs
In WKY rats using 50 cycles of PCR, we failed to amplify the JAM-1 mRNA transcript containing 3'UTR (nucleotides 1145 to 1385 in BC065309; JAM-1/1145 to 1385) in the rostral ventrolateral medulla, supraoptic nuclei, cerebellum, liver, and heart. In contrast, expression was evident in the same tissues of the SHR (Figure 1 and 2
). However, the JAM-1/1145 to 1385 transcript was detectable in the paraventricular nuclei, cerebral cortex, lung, kidney, spleen, and skeletal muscle of WKY rats but was clearly less abundant than that present in the SHR (Figures 1 and 2). Using real-time RT-PCR, we confirmed that the threshold cycle of ß-actin of these tissues was the same between SHRs and WKY rats, indicating that the total RNA concentration in each sample was identical (data not shown). Because of its role in central control of arterial pressure and baroreceptor reflex function, all of the remaining studies focused on the NTS.
|
|
Quantitative Comparison of the Levels of JAM-1 Gene Expression in the NTS of WKY Rats and SHRs
In the NTS, the level of JAM-1 mRNA transcript representing the protein-coding sequences (JAM-1/430 to 652) was significantly higher in both young and adult SHRs compared with age-matched WKY rats (adult WKY rats and SHRs: 1.08±0.14 versus 2.86±0.57, respectively, n=10 for each strain, P<0.01; young WKY rats and SHRs, 1.01±0.06 versus 1.59±0.13 respectively, n=10 for each strain, P<0.01; Figure 3). With regard to JAM-1/1145 to 1385, we failed to amplify it in the NTS of both young and adult WKY rats. In contrast, it was present in the NTS of SHRs in both young and adult animals (Figure 3). It was notable that the threshold cycle of ß-actin was the same between the 2 strains of rats (Figure 3), indicating that the total RNA concentration in each sample was identical.
|
Immunocytochemical Evidence for JAM-1 Presence in the NTS of SHRs and WKY Rats
Although in the commissural NTS some JAM-1 immunoreactivity was detectable in WKY rats, it was clearly lower compared with the SHRs in all 6 of the rats studied (compare Figure 4A with 4B). Moreover, in the SHRs but not WKY rats, JAM-1 was extensively colocalized with RECA-1, a marker for endothelial cells consistent with JAM-1 expression in endothelium (Figure 4C).
|
Comparison of Levels of JAM-3, ICAM-1, and Vascular Cell Adhesion Molecule-1 Gene Expression in the NTS of WKY Rats and SHRs
With the heightened mRNA of JAM-1 in the NTS of the SHRs, we ascertained the specificity of the differential expression by comparing it with other vascular adhesion molecules. However, in both young and adult WKY rats and SHRs, there were no differences in the level of JAM-3, ICAM-1, and vascular cell adhesion molecule-1 gene expression in the NTS (see the data supplement), suggesting that the upregulation of JAM-1 in the SHR was specific.
Adenoviral Expression of JAM-1 in the NTS of the WKY Rat
We next tested for any functional impact of JAM-1 expression on arterial pressure regulation. With JAM-1 being upregulated in the NTS of the SHR (compared with WKY rats), we decided to overexpress it in the NTS of WKY rats. Before viral injection, baseline levels of SBP, HR, and sBRG in the Ade-CMV-JAM-1 group (n=6) were 120±4 mm Hg, 360±8 bpm, and –2.31±0.20 bpm/mm Hg, respectively. These values were not different from those of the Ade-CMV-eGFP group (n=6; SBP, 116±3 mm Hg; HR, 360±7 bpm; sBRG, –1.99±0.13 bpm/mm Hg; Figure 5). Five to 7 days after injection of the Ade-CMV-JAM-1, SBP significantly increased (control data above; 7 days after viral transduction: 132±4 mm Hg; P<0.01), whereas no changes were found in the SBP of the Ade-CMV-eGFP group (control data above; 7 days after viral transduction: 121±3 mm Hg). The average maximum increment of SBP occurred between 5 and 7 days and was 16.2±2.8 mm Hg; this value was significantly higher than that in the Ade-CMV-eGFP group (4.7±2.9 mm Hg; P<0.05). In contrast, HR was significantly decreased, whereas sBRG did not change 5 to 7 days after viral transduction in the Ade-CMV-JAM-1 group (7 days after viral transduction: HR, 311±8 bpm, P<0.01; sBRG, –2.34±0.27 bpm/mm Hg, P value not significant; Figure 5). Fourteen days after Ade-CMV-JAM-1 transduction, the SBP remained elevated compared with control levels (ie, 130±5 mm Hg; P<0.05), whereas HR changes returned to pretransfection levels (361±10 bpm; Figure 5). In the Ade-CMV-eGFP group, all of these parameters were unaffected by viral transduction except for HR, which showed a transient bradycardia on day 5 after viral injection (eg, from 360±7 to 304±13 bpm; P<0.01; Figure 5).
|
Location of NTS Sites Transduced With Ad-CMV-JAM-1 and AdV-CMV-eGFP
JAM-1 immunoreactivity was elevated after Ad-CMV-JAM-1 transduction compared with endogenous JAM-1 immunoreactivity (Figure 4). Numerous NTS cells including glia and blood vessels were immunopositive for JAM-1 on day 7 of posttransduction (Figure 4). In contrast, JAM-1 immunoreactivity in Ad-CMV-eGFP rats (data not shown) was equivalent to control (naïve rats) as depicted in Figure 4A. Moreover, based on the localization of JAM-1 immunoreactivity and eGFP expression, highly comparable NTS regions were transduced with both viruses. These regions spanned –13.8 to –14.6 mm relative to Bregma (ie, 400 µm rostral and caudal to calamus scriptorius), 300 to 800 µm from midline and 400 to 800 µm below the dorsal surface of the medulla.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We have demonstrated that expression of JAM-1 mRNA is elevated in multiple organs in the SHR compared with WKY rat. In the brain stem (as exemplified in the NTS) JAM-1 protein is localized in endothelial cells, and the level of expression is higher quantitatively in the SHR compared with WKY rats. To assess the functional consequence of heightened JAM-1 expression in the NTS, we used an adenovirus to chronically overexpress JAM-1 in this brain stem structure of normotensive WKY rats and found that this produces hypertension, consistent with a prohypertensive role of JAM-1.
JAM-1 Expression: SHRs Versus WKY Rats
With regard to the JAM-1/1145 to 1385 transcript, we found that the level of this transcript in WKY varied between organs, whereas it was present in all of the organs analyzed in the SHR. Regarding the NTS, JAM-1/1145 to 1385 transcript was not detectable in WKY rats, whereas it was clearly present in the SHR. This indicates that, in the SHR, JAM-1 mRNA is spliced differently to WKY rats. In the NTS (and other brain areas studied), it appears to have an extended 3'UTR, a known feature present on many translationally efficient mRNAs. Alternatively, it is possible that the WKY transcripts lack 5'UTR because of differences in the transcription termination mechanism. When primers for the protein-coding part of JAM-1 mRNA were used (JAM-1/430 to 652), the transcript could be clearly identified in the NTS of WKY rats, although the level of expression was much lower than that of SHRs (see Figure 3). These results suggest that in normotensive WKY rats, a significant fraction of JAM-1 mRNA lacks 3'UTR sequences, annotated in GeneBank BC065309 entry, making it unstable and effectively reducing the amount of JAM-1 mRNA available for protein expression. Furthermore, processing of JAM-1 mRNA is shifted toward the 3'UTR-containing transcript in many brain regions and bodily organs in the SHR compared with the WKY rat. JAM-1 is one of the proteins that forms the tight junction in both endothelial cells16 and some types of epithelial cells.15 Our immunocytochemistry data demonstrated that JAM-1 protein in the brain stem (as exemplified in NTS) is abundantly expressed in endothelial cells where the level of expression is higher in SHRs compared with WKY rats. Importantly, JAM-1 expression in the SHR is not secondary to hypertension, because prehypertensive SHRs also showed a high level of JAM-1 gene expression, at least in NTS.
Under certain conditions endothelial JAM-1 shows a transmembrane luminal orientation thereby protruding into the bloodstream. With its leukocyte binding site (via a leukocyte function-associated antigen-1), JAM-1 is known to cause leukocyte adhesion.15,19,24–26 In addition, JAM-1 can activate platelet aggregation.15,26 In this context, it is curious that leukocyte adhesion27 and platelet aggregability28 are enhanced in both the SHRs and humans with essential hypertension. All of these abnormalities can cause accumulation of these cells leading to release of inflammatory mediators, atherosclerosis, and atherothrombosis.17,19,29 One outcome of the latter is an increased total peripheral resistance that contributes to the hypertension.18,20,30 In addition, any inflammatory response may, in part, be because of altered gene/protein expression in endothelial cells affecting, for example, JAM-1 expression, thereby increasing the adhesion of blood cell types to the vessel wall.17,25 This is entirely consistent with leukocyte adhesion after JAM-1 expression in the NTS of the WKY rat, which is normally devoid of such pathology (see the data supplement).
Another highly expressed molecule in endothelial cells is ICAM-1, which is upregulated in carotid arteries in the SHR.27 However, we failed to detect a high level of ICAM-1 gene expression in the NTS of SHRs, compared with WKY rats, indicating that the level of expression of ICAM-1 in the SHR could be vascular bed specific (see the data supplement). Similarly, the levels of expression of JAM-3 and vascular cell adhesion molecule-1 in the NTS were not different between the SHR and WKY rat. These results suggest that the high level of JAM-1 mRNA in the NTS of the SHR is specific to this type of endothelial adhesion molecule and not related to a general inflammatory reaction.
JAM-1 Expression in the NTS and Hypertension
A functional role for JAM-1 for regulating arterial pressure was tested by overexpressing it in the NTS of adult normotensive WKY rats using adenoviral gene transfer. This resulted in abundant JAM-1 expression in the NTS, including glia and endothelial cells (Figure 4). Five days after viral injection, SBP was significantly higher than control rats and remained elevated into day 14 after viral injection (Figure 5). In contrast to the SBP, sBRG did not change over this period, suggesting that JAM-1 in the NTS was affecting neural mechanisms controlling the set point of arterial pressure independent of alterations in baroreflex sensitivity. However, whether the gain of the baroreceptor reflex sympathetic vasoconstrictor component was modified remains unknown, because we did not test this. In addition, HR was significantly lower between 5 and 7 days after viral transduction with Ad-CMV-JAM-1 but, unlike SBP, returned to control 2 weeks later. The transient fall in HR may be mediated by the cardiac baroreflex in response to the rising level of arterial pressure. Fourteen days after viral transduction, however, the operating point of the reflex could reset to a higher level of arterial pressure and, hence, the level of HR returns to normal. It should be noted that, at least for the first 5 days after Ad-CMV-JAM-1 transduction, the fall in HR may be a consequence of surgery and viral induced transduction in the NTS, as we have reported previously.11
The increase in SBP in the WKY rats after Ad-CMV-JAM-1 overexpression was associated with an increase in both the low frequency:high frequency of HR variability and low frequency+very low frequency power of SBP variability, suggesting activation of cardiac and vasomotor sympathetic activity, respectively (see the data supplement). It should be noted that the low frequency:high frequency of HR variability increased, whereas HR was decreased 7 days after Ad-CMV-JAM-1 transduction. The fall in HR may be because of an enhanced vagal tone, because the high-frequency power of HR variability increased after Ad-CMV-JAM-1 transduction (see the data supplement).
Possible Mechanisms by Which JAM-1 in NTS Elevates Arterial Pressure
Our findings show that high level of JAM-1 expression at the level of NTS can cause hypertension in WKY rats. The question of how this arises comes about. We have recently described that adenoviruses with the human CMV promoter drive extremely low levels of gene expression in most NTS neurons.31 On the other hand, these vectors clearly transduce local vasculature.11 Based on evidence that JAM-1 can cause leukocyte and platelet adhesion in the peripheral circulation,24–26 it was necessary to assess whether this could occur within the brain after inducing JAM-1 overexpression. The data that we present suggest that, at least in NTS, JAM-1 can induce leukocyte binding (see the data supplement). It remains unclear what, if any, effect this would have on NTS neurons impinging on downstream neuronal networks controlling sympathetic activity. Nevertheless, these results raise the intriguing and novel possibility that there is a link between high levels of leukocyte/platelet adhesion in the brain stem and excessive levels of sympathetic nerve activity. Thus, once adhered to the endothelium, leukocytes (and platelets) release both cytokines and reactive oxygen species, such as superoxide. These are established products from such cells32,33 and are known to activate brain stem cardiovascular neurons.34,35 Because some types of cytokines can cross the blood–brain barrier,36 it now becomes pertinent to understand their actions on brain stem circuitry regulating the set point control of arterial pressure. In addition, leukocyte accumulation in capillaries may provide a significant obstacle to blood flow, resulting in localized ischaemia.37 The latter could further enhance cytokine and reactive oxygen species production from affected endothelial cells.38,39 The functional significance of cytokines, chemokines, and reactive oxygen species activation within the central nervous system has been studied40–43 and includes modulation of central neurotransmitters (eg, noradrenaline,44 5-hydroxytryptamine,45 glutamate,46 and 
-aminobutyric acid46,47), effects on neuronal differentiation/growth,48 and synaptic plasticity.49 Such actions might affect brain stem circuitry regulating sympathetic activity that may lead to significant alterations in blood pressure control.
Perspectives
We have revealed that there is widespread JAM-1 expression in the SHR compared with the WKY rat. Increased JAM-1 protein expression in brain stem structure(s) regulating arterial pressure, such as the NTS, could contribute to hypertension. It remains to be established whether a similar scenario applies to other brain regions of the SHR, such as the circumventricular organs, hypothalamus, and rostral ventrolateral medulla, and also peripheral tissues, such as the kidney and heart, and how this may contribute to hypertension.
|
Acknowledgments |
|---|
J.F.R.P. received a Royal Society Wolfson Research Merit Award.
Sources of Funding
The study was financially supported by the British Heart Foundation (BS/93003) and National Institutes of Health (R01 HL033610-18).
Disclosures
None.
Received December 5, 2006; first decision December 12, 2006; accepted March 15, 2007.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton P, Brown C, Roccella EJ. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension. 1995; 26: 60–69.
2. Delva P, Lechi A, Pastori C, Degan M, Sheiban I, Montesi G, Pea M, Meneguzzi A, Menegazzi M. Collagen I and III mRNA gene expression and cell growth potential of skin fibroblasts in patients with essential hypertension. J Hypertens. 2002; 20: 1393–1399.[CrossRef][Medline] [Order article via Infotrieve]
3. Chon H, Gaillard CA, van der Meijden BB, Dijstelbloem HM, Kraaijenhagen RJ, van Leenen D, Holstege FC, Joles JA, Bluyssen HA, Koomans HA, Braam B. Broadly altered gene expression in blood leukocytes in essential hypertension is absent during treatment. Hypertension. 2004; 43: 947–951.
4. Egan BM. Neurogenic mechanisms initiating essential hypertension. Am J Hypertens. 1989; 2: 357S–362S.[Medline] [Order article via Infotrieve]
5. Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA. Sympathetic neural mechanisms in white-coat hypertension. J Am Coll Cardiol. 2002; 40: 126–132.
6. Grassi G. Counteracting the sympathetic nervous system in essential hypertension. Curr Opin Nephrol Hypertens. 2004; 13: 513–519.[CrossRef][Medline] [Order article via Infotrieve]
7. Judy WV, Farrell SK. Arterial baroreceptor reflex control of sympathetic nerve activity in the spontaneously hypertensive rat. Hypertension. 1979; 1: 605–614.
8. Lundin S, Ricksten SE, Thoren P. Renal sympathetic activity in spontaneously hypertensive rats and normotensive controls, as studied by three different methods. Acta Physiol Scand. 1984; 120: 265–272.[Medline] [Order article via Infotrieve]
9. Doba N, Reis DJ. Acute fulminating neurogenic hypertension produced by brainstem lesions in the rat. Circ Res. 1973; 32: 584–593.
10. Talman WT, Perrone MH, Reis DJ. Acute hypertension after the local injection of kainic acid into the nucleus tractus solitarii of rats. Circ Res. 1981; 48: 292–298.
11. Waki H, Kasparov S, Murphy D, Paton JF. Endothelial nitric oxide synthase in nucleus tractus solitarii contributes to hypertension in spontaneously hypertensive rats. Hypertension. 2006; 48: 644–650.
12. Paton JF. The Sharpey-Schafer prize lecture: nucleus tractus solitarii: integrating structures. Exp Physiol. 1999; 84: 815–833.[Abstract]
13. Sunagawa K, Sato T, Kawada T. Integrative sympathetic baroreflex regulation of arterial pressure. Ann N Y Acad Sci. 2001; 940: 314–323.[Medline] [Order article via Infotrieve]
14. Waki H, Kasparov S, Miyake M, Katahira K, Liu B, Murphy D, Paton JF. Gene expression profiles in the nucleus tractus solitarii of the spontaneously hypertensive rat. J. Physiol. 2004;560P:PC6. Available at: http://www.physoc.org/publications/proceedings/archive/article.asp?ID=J%20Physiol%20560PPC6. Accessed August 1, 2006.
15. Ebnet K, Suzuki A, Ohno S, Vestweber D. Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci. 2004; 117: 19–29.
16. Huber JD, Egleton RD, Davis TP. Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci. 2001; 24: 719–725.[CrossRef][Medline] [Order article via Infotrieve]
17. Ostermann G, Fraemohs L, Baltus T, Schober A, Lietz M, Zernecke A, Liehn EA, Weber C. Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium: inhibition by soluble JAM-A. Arterioscler Thromb Vasc Biol. 2005; 25: 729–735.
18. Fukuda S, Yasu T, Kobayashi N, Ikeda N, Schmid-Schonbein GW. Contribution of fluid shear response in leukocytes to hemodynamic resistance in the spontaneously hypertensive rat. Circ Res. 2004; 95: 100–108.
19. Babinska A, Kedees MH, Athar H, Ahmed T, Batuman O, Ehrlich YH, Hussain MM, Kornecki E. F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in inflammatory thrombosis. Thromb Haemost. 2002; 88: 843–850.[Medline] [Order article via Infotrieve]
20. Virdis A, Ghiadoni L, Sudano I, Buralli S, Salvetti G, Taddei S, Salvetti A. Endothelial function in hypertension: role of gender. J Hypertens. 2002; 20 (suppl): S11–S16.[CrossRef]
21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods. 2001; 25: 402–408.[CrossRef][Medline] [Order article via Infotrieve]
22. Waki H, Kasparov S, Wong LF, Murphy D, Shimizu T, Paton JFR. Chronic inhibition of endothelial nitric oxide synthase activity in nucleus tractus solitarii enhances baroreceptor reflex in conscious rats. J Physiol. 2003; 546: 233–242.
23. Waki H, Katahira K, Polson JW, Kasparov S, Murphy D, Paton JFR. Automation of analysis of cardiovascular autonomic function from chronic measurements of arterial pressure in conscious rats. Exp Physiol. 2006; 91: 201–213.
24. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3: 151–158.[CrossRef][Medline] [Order article via Infotrieve]
25. Fraemohs L, Koenen RR, Ostermann G, Heinemann B, Weber C. The functional interaction of the beta 2 integrin lymphocyte function-associated antigen-1 with junctional adhesion molecule-A is mediated by the I domain. J Immunol. 2004; 173: 6259–6264.
26. Naik UP, Ehrlich YH, Kornecki E. Mechanisms of platelet activation by a stimulatory antibody: cross-linking of a novel platelet receptor for monoclonal antibody F11 with the Fc gamma RII receptor. Biochem J. 1995; 310: 155–162.[Medline] [Order article via Infotrieve]
27. Liu Y, Liu T, McCarron RM, Spatz M, Feuerstein G, Hallenbeck JM, Siren AL. Evidence for activation of endothelium and monocytes in hypertensive rats. Am J Physiol. 1996; 270: H2125–H2131.[Medline] [Order article via Infotrieve]
28. Tomoda F, Takata M, Kagitani S, Kinuno H, Yasumoto K, Tomita S, Inoue H. Different platelet aggregability during mental stress in two stages of essential hypertension. Am J Hypertens. 1999; 12: 1063–1070.[CrossRef][Medline] [Order article via Infotrieve]
29. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005; 115: 3378–3384.[CrossRef][Medline] [Order article via Infotrieve]
30. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med. 1997; 48: 489–509.[CrossRef][Medline] [Order article via Infotrieve]
31. Lonergan T, Teschemacher AG, Hwang DY, Kim KS, Pickering AE, Kasparov S. Targeting brain stem centers of cardiovascular control using adenoviral vectors: impact of promoters on transgene expression. Physiol Genomics. 2005; 20: 165–172.
32. Crockett-Torabi E, Ward PA The role of leukocytes in tissue injury. Eur J Anaesthesiol. 1996; 13: 235–246.[CrossRef][Medline] [Order article via Infotrieve]
33. Krotz F, Sohn HY, Pohl U. Reactive oxygen species: players in the platelet game. Arterioscler Thromb Vasc Biol. 2004; 24: 1988–1996.
34. Mayorov DN, Head GA, De Matteo R. Tempol attenuates excitatory actions of angiotensin II in the rostral ventrolateral medulla during emotional stress. Hypertension. 2004; 44: 101–106.
35. Zimmerman MC, Lazartigues E, Sharma RV, Davisson RL. Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res. 2004; 95: 210–206.
36. Banks WA. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des. 2005; 11: 973–984.[CrossRef][Medline] [Order article via Infotrieve]
37. Gorbet MB, Sefton MV. Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials. 2004; 25: 5681–5703.[CrossRef][Medline] [Order article via Infotrieve]
38. Michiels C, Arnould T, Remacle J. Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta. 2000; 1497: 1–10.[Medline] [Order article via Infotrieve]
39. Ishida I, Kubo H, Suzuki S, Suzuki T, Akashi S, Inoue K, Maeda S, Kikuchi H, Sasaki H, Kondo T. Hypoxia diminishes toll-like receptor 4 expression through reactive oxygen species generated by mitochondria in endothelial cells. J Immunol. 2002; 169: 2069–2075.
40. Valencia A, Moran J. Reactive oxygen species induce different cell death mechanisms in cultured neurons. Free Radic Biol Med. 2004; 36: 1112–1125.[CrossRef][Medline] [Order article via Infotrieve]
41. Paton JF, Kasparov S, Paterson DJ. Nitric oxide and autonomic control of heart rate: a question of specificity. Trends Neurosci. 2002; 25: 626–631.[CrossRef][Medline] [Order article via Infotrieve]
42. Szelenyi J. Cytokines and the central nervous system. Brain Res Bull. 2001; 54: 329–338.[CrossRef][Medline] [Order article via Infotrieve]
43. Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: Actions and mechanisms of action. Trends Neurosci. 1995; 18: 130–136.[CrossRef][Medline] [Order article via Infotrieve]
44. Dunn AJ. Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism parallelling the increased plasma corticosterone. Life Sci. 1988; 43: 429–435.[CrossRef][Medline] [Order article via Infotrieve]
45. Dunn AJ. Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. J Pharmacol Exp Ther. 1992; 261: 964–969.
46. Miller LG, Fahey JM. Interleukin-1 modulates GABAergic and glutamatergic function in brain. Ann N Y Acad Sci. 1994; 739: 292–298.[Medline] [Order article via Infotrieve]
47. Sah R, Galeffi F, Ahrens R, Jordan G, Schwartz-Bloom RD. Modulation of the GABA(A)-gated chloride channel by reactive oxygen species. J Neurochem. 2002; 80: 383–391.[CrossRef][Medline] [Order article via Infotrieve]
48. Sawada M, Suzumura A, Marunouchi T. Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci. 1995; 13: 253–264.[CrossRef][Medline] [Order article via Infotrieve]
49. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006; 440: 1054–1059.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. J Rickard and M. J Young Corticosteroid receptors, macrophages and cardiovascular disease J. Mol. Endocrinol., June 1, 2009; 42(6): 449 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Sen, N. Tyagi, P. K. Patibandla, W. L. Dean, S. C. Tyagi, A. M. Roberts, and D. Lominadze Fibrinogen-induced endothelin-1 production from endothelial cells Am J Physiol Cell Physiol, April 1, 2009; 296(4): C840 - C847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. R. Paton, C. J. Dickinson, and G. Mitchell Harvey Cushing and the regulation of blood pressure in giraffe, rat and man: introducing 'Cushing's mechanism' Exp Physiol, January 1, 2009; 94(1): 11 - 17. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zubcevic, H. Waki, C. Diez-Freire, A. Gampel, M. K. Raizada, and J. F.R. Paton Chronic Blockade of Phosphatidylinositol 3-Kinase in the Nucleus Tractus Solitarii Is Prohypertensive in the Spontaneously Hypertensive Rat Hypertension, January 1, 2009; 53(1): 97 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lopez-Campistrous, L. Hao, W. Xiang, D. Ton, P. Semchuk, J. Sander, M. J. Ellison, and C. Fernandez-Patron Mitochondrial Dysfunction in the Hypertensive Rat Brain: Respiratory Complexes Exhibit Assembly Defects in Hypertension Hypertension, February 1, 2008; 51(2): 412 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M.Y. Cheung and K. L. Ong Junctional Adhesion Molecule-1 May Have a Wider Role in Cardiovascular Disease Hypertension, August 1, 2007; 50(2): e22 - e22. [Full Text] [PDF]
|
|
|
|
|
|
H. Waki and J. F.R. Paton Response to Junctional Adhesion Molecule-1 May Have a Wider Role in Cardiovascular Disease Hypertension, August 1, 2007; 50(2): e23 - e23. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||