Abstract 343: Vascular Inflammation in Two Rat Models of Arterial Hypertension is Promoted by Coagulation FXI

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jeremy Lagrange ◽  
Sabine Kossmann ◽  
Andreas Daiber ◽  
Matthias Oelze ◽  
Brett Monia ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Hypertension ◽  
Feedback Loop ◽  
Thrombin Generation ◽  
Vascular Reactivity ◽  
Platelet Rich Plasma ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Experimental Hypertension

Backgroud: Interactions of platelets, leukocytes and the vessel wall play pivotal roles in activating coagulation and precipitating thrombosis. We were recently able to uncover an angiotensin II (ATII) driven factor XI (FXI)-thrombin amplification loop leading to vascular injury in experimental hypertension in mice. Objective: We wanted was to explore the role of thrombin-FXI feedback loop in different models of arterial hypertension in rats. Methods: ATII treated wistar rats (1mg·kg -1 ·d -1 for 7 days using osmotic minipumps) and 5/6 nephrectomized were used for this study. During 2 weeks rats were treated with a FXI antisense oligonucleotide (ASO) (1 week after nephrectomy or 2 weeks before ATII pump implantation, respectively). Blood pressure was recorded with tail cuff measurement. Fluorescence oxidative microtopography was used to evaluate vascular ROS production. Vascular reactivity was assessed in isolated aortic segment. Calibrated automated thrombography was used to measure thrombin generation. Results: In ATII infused rats as well as 5/6 nephrectomized rats vascular dysfunction related to hypertension was attenuated when rats were treated with FXI ASO. Hypertension induced VCAM-1 expression was normalize with inhibition of FXI. ROS formation was normalized in ATII infused rats as well as 5/6 nephrectomized treated with FXI ASO. Thrombin generation in platelet rich plasma from 5/6 nephrectomized rats was completely abolished when FXI was inhibited. Finally the overall blood pressure increase was abrogated by FXI ASO treatment in 5/6 nephrectomized rats. Conclusion: FXI plays a critical role in a FXI-thrombin feedback loop in hypertension. This pathway is relevant in mice and rats and we were able to very recently obtain the first conclusive results in humans. FXI could be a novel therapeutic target to interrupt this heterotypic cellular coagulation-inflammatory circuit.

scholarly journals Platelet-Localized FXI Promotes a Glycoprotein Ib Alpha Dependent Feedback Loop in Arterial Hypertension and Vascular Inflammation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2192-2192
Author(s):  
Jeremy Lagrange ◽  
Sabine Kossmann ◽  
Jäckel Sven ◽  
Jurk Kerstin ◽  
Moritz Ehlken ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Antisense Oligonucleotide ◽  
Vessel Wall ◽  
Feedback Loop ◽  
Thrombin Generation ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Ros Production

Abstract Backgroud: Vascular inflammation is a hallmark of atherosclerosis and arterial and venous thromboembolic disease. Arterial hypertension is a highly significant risk factor for death and cardiovascular disease. High levels of angiotensin II (ATII) cause arterial hypertension by a complex inflammatory pathway requiring leukocyte recruitment and reactive oxygen species production within the vessel wall. Interactions of platelets, leukocytes and the vessel wall play pivotal roles in activating coagulation and precipitating thrombosis. Platelets provide a pro-coagulant surface for amplified thrombin generation in hemostasis and thrombosis, and play important roles in vascular inflammation by preserving vascular integrity. They also promote leukocyte recruitment in wire injury and angiogenesis models through glycoprotein Ib alpha (GPIbalpha) interacting with the integrin alphaMbeta2 (CD11b/CD18 or Mac-1) on leukocytes and regulate monocyte and neutrophil activation. How platelets, coagulation factors, leukocytes and the vessel wall cooperate to promote vascular inflammation in arterial hypertension is unclear. Objective: The aim of this work was to explore the roles of TF, FXI, FXII, thrombin and platelet GPIbalpha on inflammatory monocyte-driven vascular dysfunction and arterial hypertension in ATII infused mice and rats as well as in 5/6 nephrectomized (5/6Nx) rats. Methods: FXII-/-, FXI-/-, and hIL-4R/Ibalpha mice and 5/6NX rats were used for this study. Mice and rats where treated with ATII (1 mg×kg-1 ×d-1 for 7 days) using osmotic minipumps. Blood pressure was recorded using tail cuff measurement and telemetry carotid implants. To assess vasodilator properties, isolated aortic segments were mounted to force transducers in organ chambers to test their response to acetylcholine (ACh) and glyceryl trinitrate (GTN). ROS production was quantified within the aorta using dihydroethidium-derived fluorescence. Thrombin generation in platelet rich plasma (PRP) was measured using calibrated automated thrombography. Results: ATII induces an upregulation of tissue factor, thrombin-dependent endothelial cell VCAM-1 expression and integrin alpha4- and platelet-dependent leukocyte adhesion to arterial conductance vessels. Depletion of platelets using an anti-GPIbalpha antibody as well as injection of anti-Mac-1 directed against the CD11b/CD18 integrin on leukocytes similarly prevented leukocyte rolling and adhesion. Reduced vascular recruitment of leukocytes was paralleled by diminished vascular ROS production assessed by the superoxide-sensitive dye dihydroethidium. ATII-induced vascular dysfunction unexpectedly involved the activation of FXI but not FXII. Moreover, inhibition of FXI synthesis attenuates blood pressure increase in response to ATII. The platelet FXI receptor GPIbalpha supports the upregulation of thrombin feedback activation in ATII-treated mice. Blockade of TF during ATII administration attenuated both endothelial dysfunction (acetylcholine concentration-relaxation curves) and smooth muscle dysfunction as demonstrated by improved vascular relaxation in response to the endothelium independent vasodilator glyceryl trinitrate and reduced ROS within the vessel wall. Five/6Nx rats had endothelial dysfunction that was prevented by FXI Antisense oligonucleotide. Thrombin-induced thrombin generation was increased in PRP of 5/6 Nx rats and markedly diminished by FXI Antisense oligonucleotide, mimicking the results from ATII-infused mice. Conclusion: Our results reveal a critical role of platelet GPIbalpha to promote localized thrombin amplification and a FXI-thrombin feedback loop in ATII-induced vascular inflammation. Importantly, pharmacologic inhibition of FXI synthesis is sufficient to prevent thrombin propagation on platelets, to reduce vessel wall leukocyte infiltration, and to diminish ATII-induced endothelial dysfunction and arterial hypertension in mice and rats.Targeting FXI could be a novel therapeutic possibility to interrupt this heterotypic cellular coagulation-inflammatory circuit. Disclosures Monia: Isis Pharmaceuticals: Employment.

scholarly journals Vascular and renal function in experimental thyroid disorders

2006 ◽  
Vol 154 (2) ◽  
pp. 197-212 ◽  
Author(s):  
Félix Vargas ◽  
Juan Manuel Moreno ◽  
Isabel Rodríguez-Gómez ◽  
Rosemary Wangensteen ◽  
Antonio Osuna ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Renal Function ◽  
Thyroid Hormones ◽  
Arterial Hypertension ◽  
Vascular Resistance ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Experimental Hypertension ◽  
Water Metabolism

This review focuses on the effects of thyroid hormones in vascular and renal systems. Special emphasis is given to the mechanisms by which thyroid hormones affect the regulation of body fluids, vascular resistance and, ultimately, blood pressure. Vascular function is markedly affected by thyroid hormones that produce changes in vascular reactivity and endothelial function in hyper- and hypothyroidism. The hypothyroid state is accompanied by a marked decrease in sensitivity to vasoconstrictors, especially to sympathetic agonists, alteration that may play a role in the reduced blood pressure of hypothyroid rats, as well as in the preventive effects of hypothyroidism on experimental hypertension. Moreover, in hypothyroid rats, the endothelium-dependent and nitric oxide donors vasodilation is reduced. Conversely, the vessels from hyperthyroid rats showed an increased endothelium-dependent responsiveness that may be secondary to the shear-stress induced by the hyperdynamic circulation, and that may contribute to the reduced vascular resistance characteristic of this disease. Thyroid hormones also have important effects in the kidney, affecting renal growth, renal haemodynamics, and salt and water metabolism. In hyperthyroidism, there is a resetting of the pressure-natriuresis relationship related to hyperactivity of the reninangiotensin system, which contributes to the arterial hypertension associated with this endocrine disease. Moreover, thyroid hormones affect the development and/or maintenance of various forms of arterial hypertension. This review also describes recent advances in our understanding of thyroid hormone action on nitric oxide and oxidative stress in the regulation of cardiovascular and renal function and in the long-term control of blood pressure.

Abstract 532: New Agonist of A2a Receptor Reduces Ventricular and Vascular Dysfunction in Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Allan K Alencar ◽  
Sharlene L Pereira ◽  
Arthur E Kummerle ◽  
Sharon S Langraf ◽  
Celso Caruso-Neves ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Systolic Pressure ◽  
Pulmonary Tissue ◽  
A2a Receptor ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance with subsequent remodeling and right ventricular hypertrophy. Vascular reactivity and ventricular function were investigated in rats with monocrotaline-induced PAH and treated with a new N-acylhydrazone derivative named as LASSBio-1359. METHODS: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single i.p. injection of monocrotaline (MCT) (60 mg/kg) for PAH induction and were randomly divided in groups which were treated with: saline, vehicle and LASSBio-1359 (50 mg/kg p.o.). After 14 days of treatment, some parameters were evaluated: pulmonary acceleration time (PAT); right ventricular systolic pressure (RVSP); vascular reactivity to acetylcholine; expression of iNOS in pulmonary tissue; wall thickness of pulmonary artery (PAWT). Results: PAT (ms) was increased from 26.2 ± 2.8 to 41.3 ± 3.9 in PAH group treated with vehicle (n=8, p<0.05) and was reduced to 24.2 ± 1.7 when PAH group was treated with LASSBio-1359. RVSP (mmHg) increased from 26.0 ± 2.0 to 55.2 ± 2.3 in PAH group (p<0.05) but was similar to control after treatment with LASSBio-1359 (31.8 ± 2.3 mm Hg). Ratio of right ventricle and body weight (mg/g) was 0.66 ± 0.02, 1.63 ± 0.16 and 0.87 ± 0.10 for control, vehicle- and LASSBio-1359-treated PAH groups, respectively. PAH promoted ventricular dysfunction which was reduced by LASSBio-1359. The pulmonary artery maximum relaxation (%) was 57.3 ± 5.5, 43.6 ± 1.2 and 61.4 ± 8.4 for control, vehicle and LASSBio-1359-treated groups indicating that PAH promoted endothelium injury which was recovered by LASSBio-1359. iNOS expression in pulmonary tissue was increased from 0.48 ± 1.31 to 0.98 ± 3.14 in PAH group and reduced to 0.53 ± 1.83 in rats treated with LASSBio-1359. The PAWT (%) were increased from 74.1 ± 1.3 to 90.2 ± 2.7 in PAH group (p<0.05) but was 74.4 ± 1.3 when treated with LASSBio-1359. This compound showed an in vitro vasodilatory activity mediated by activation of adenosinergic A2A receptor. Conclusion: LASSBio-1359 reduced ventricular and vascular dysfunction in monocrotaline-induced PAH in rats indicating a possible new alternative to treat PAH.

scholarly journals Plasma S1P links to hypertension and biomarkers of inflammation, metabolism and cardiovascular disease – findings from a translational investigation

2020 ◽  
Author(s):  
Amra Jujic ◽  
Frank Matthes ◽  
Lotte Vanherle ◽  
Henning Petzka ◽  
Marju Orho-Melander ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Systolic Blood Pressure ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Plasma Concentrations ◽  
Human Study ◽  
Experimental Hypertension ◽  
Study Cohort ◽  
Markers Of Inflammation

Recent studies identified sphingosine-1-phosphate (S1P) as an important player in immune cell trafficking and vascular dysfunction contributing to the development and progression of overt hypertension. Although targeting S1P signaling revealed therapeutic potential in different experimental hypertension studies, validations of S1P-blood pressure associations in humans are lacking. In a translational approach, we explored the associations between plasma S1P, quantified using LC-MS, and blood pressure in a family-based study cohort (MOS) study, and in a longitudinally conducted murine hypertension cohort. In MOS, linear multivariate regression analyses showed that plasma S1P associates with increased systolic blood pressure. Study subjects with systolic blood pressure ≥ 140 mmHg presented with significantly higher S1P plasma concentrations compared to subjects with blood pressure ≤ 120 mmHg independent of age and sex. The S1P-blood pressure association was validated in a murine model where plasma S1P increased with systolic blood pressure. In a sub-sample of the human study population, proteomic profiling for markers of inflammation, metabolism and cardiovascular disease was carried out using proximity Extension Assays. Testing S1P associations revealed multiple significant interactions, some of them with marked sex-specificity. Amongst them, interleukin 18, which exerts apparent vascular and immune responses during hypertension and associates to adverse cardiovascular events, strongly correlates with plasma S1P concentrations in females but not males in both humans and mice. In vitro and ex vivo validation of S1P effects on endothelial and monocytic cells of murine or human origin and resistance arteries isolated from mice disclosed augmented expression of different vascular dysfunction and inflammation markers in response to exogenously added S1P. Taken together, our translational findings strongly suggest a link between plasma S1P and systolic blood pressure as well as several inflammation and cardiovascular disease biomarkers in humans, encouraging further studies to investigate S1Ps potential as a therapeutic target in hypertensive disease.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

Critical opening pressure and reactivity of tail vessels in conscious hypertensive rats

1976 ◽  
Vol 54 (3) ◽  
pp. 314-321
Author(s):  
A. C. Darke ◽  
P. G. Nair ◽  
P. Gaskell
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Vascular Reactivity ◽  
Experimental Hypertension ◽  
Hypertensive Rats ◽  
Opening Pressure ◽  
Critical Opening ◽  
Resistance Vessels ◽  
Before And After ◽  
Desoxycorticosterone Acetate

The possible role of increased vascular reactivity in the mechanism of experimental hypertension was studied by measurements of the critical opening pressure (COP) of tail vessels in conscious rats. In hypertension induced by administration of desoxycorticosterone acetate (DOCA) and replacement of the drinking water by 1% NaCl solution (DOCA–NaCl hypertension), and in one-kidney Goldblatt renovascular hypertension, the raised level of blood pressure was associated with an increased COP of the tail vessels when measured both before and after ganglionic blockade. In rats treated with either DOCA alone or 1% NaCl alone there was no significant increase in systolic blood pressure (SBP) or COP relative to the corresponding controls. In all four experimental series intravenous infusion of angiotensin or norepinephrine in conscious ganglion-blocked rats produced dose-dependent increases in SBP and COP. In DOCA–NaCl hypertensive rats but not in renovascular hypertensives, nor in rats treated with DOCA alone or 1% NaCl alone, the increase in COP for a given increment in dose of angiotensin or norepinephrine was significantly greater than in the control rats. It is concluded that in DOCA–NaCl hypertension there is a true increase in the reactivity of the smooth muscle of the resistance vessels to angiotensin and norepinephrine. In renovascular hypertension this is not the case and other factors must therefore be involved in causing the increased blood pressure and COP.

scholarly journals Vascular Dysfunction as Target Organ Damage in Animal Models of Hypertension

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Mario Fritsch Neves ◽  
Daniel Arthur B. Kasal ◽  
Ana Rosa Cunha ◽  
Fernanda Medeiros
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Experimental Hypertension ◽  
Chronic Hypertension ◽  
No Production ◽  
Response Curves ◽  
Spontaneously Hypertensive

Endothelial dysfunction is one of the main characteristics of chronic hypertension and it is characterized by impaired nitric oxide (NO) bioactivity determined by increased levels of reactive oxygen species. Endothelial function is usually evaluated by measuring the vasodilation induced by the local NO production stimulated by external mechanical or pharmacological agent. These vascular reactivity tests may be carried out in different models of experimental hypertension such as NO-deficient rats, spontaneously hypertensive rats, salt-sensitive rats, and many others. Wire myograph and pressurized myograph are the principal methods used for vascular studies. Usually, increasing concentrations of the vasodilator acetylcholine are added in cumulative manner to perform endothelium-dependent concentration-response curves. Analysis of vascular mechanics is relevant to identify arterial stiffness. Both endothelial dysfunction and vascular stiffness have been shown to be associated with increased cardiovascular risk.

scholarly journals Double-stranded RNA and Toll-like receptor activation: a novel mechanism for blood pressure regulation

2020 ◽  
Vol 134 (2) ◽  
pp. 303-313
Author(s):  
Vanessa Dela Justina ◽  
Fernanda R. Giachini ◽  
Fernanda Priviero ◽  
R. Clinton Webb
Keyword(s):  
Blood Pressure ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Receptor Activation ◽  
Cellular Damage ◽  
Double Stranded Rna ◽  
Molecular Pattern ◽  
Inflammatory State ◽  
Potential Improvement ◽  
Rats And Mice

Abstract Toll-like receptors (TLRs), such as TLR4 and 9, recognize pathogen-associated molecular pattern (PAMPs) and danger-associated molecular patterns (DAMPs) and are associated with increased blood pressure (BP). TLR3, residing in the endosomal compartment, is activated by viral double-stranded RNA (dsRNA) leading to activation of TIR receptor domain-containing adaptor inducing IFN-β (TRIF) dependent pathway. Besides foreign pathogens, the immune system responds to endogenous markers of cellular damage such as mitochondrial dsRNA (mtdsRNA). New evidence has shown a link between dsRNA and increased BP. Moreover, TLR3 activation during pregnancy was demonstrated to develop preeclampsia-like symptoms in both rats and mice. Hence, we hypothesize that the dsRNA derived from viral nucleic acids or cellular damage (mtdsRNA) will increase the inflammatory state through activation of TLR3, contributing to vascular dysfunction and increased BP. Therefore, inhibition of TLR3 could be a therapeutic target for the treatment of hypertension with potential improvement in vascular reactivity and consequently, a decrease in BP.

scholarly journals 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

2017 ◽  
Vol 234 (1) ◽  
pp. T67-T82 ◽  
Author(s):  
Jennifer J DuPont ◽  
Iris Z Jaffe
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Kidney Injury ◽  
Vascular Pathology ◽  
The Impact

Since the mineralocorticoid receptor (MR) was cloned 30 years ago, it has become clear that MR is expressed in extra-renal tissues, including the cardiovascular system, where it is expressed in all cells of the vasculature. Understanding the role of MR in the vasculature has been of particular interest as clinical trials show that MR antagonism improves cardiovascular outcomes out of proportion to changes in blood pressure. The last 30 years of research have demonstrated that MR is a functional hormone-activated transcription factor in vascular smooth muscle cells and endothelial cells. This review summarizes advances in our understanding of the role of vascular MR in regulating blood pressure and vascular function, and its contribution to vascular disease. Specifically, vascular MR contributes directly to blood pressure control and to vascular dysfunction and remodeling in response to hypertension, obesity and vascular injury. The literature is summarized with respect to the role of vascular MR in conditions including: pulmonary hypertension; cerebral vascular remodeling and stroke; vascular inflammation, atherosclerosis and myocardial infarction; acute kidney injury; and vascular pathology in the eye. Considerations regarding the impact of age and sex on the function of vascular MR are also described. Further investigation of the precise molecular mechanisms by which MR contributes to these processes will aid in the identification of novel therapeutic targets to reduce cardiovascular disease (CVD)-related morbidity and mortality.

scholarly journals Telmisartan Lowers Elevated Blood Pressure in Psoriatic Mice without Attenuating Vascular Dysfunction and Inflammation

2019 ◽  
Vol 20 (17) ◽  
pp. 4261 ◽  
Author(s):  
Johannes Wild ◽  
Rebecca Schüler ◽  
Tanja Knopp ◽  
Michael Molitor ◽  
Sabine Kossmann ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Skin Disease ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Skin Inflammation ◽  
Severe Psoriasis ◽  
Elevated Blood Pressure ◽  
Elevated Blood ◽  
The Impact

Background: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an intensive risk-factor reduction is recommended for psoriasis patients, we aimed to elucidate the impact of the angiotensin II receptor type 1 (AT1) antagonist telmisartan in a mouse model of severe psoriasis-like skin disease. Methods and Results: Elevated blood pressure measured by tail-cuff plethysmography in mice with keratinocyte-specific IL-17A overexpression (K14-IL-17Aind/+ mice) was significantly reduced in response to telmisartan. Importantly, vascular dysfunction, as assessed by isometric tension studies of isolated aortic rings, vascular inflammation measured by flow cytometry analysis of CD45+CD11b+ immune cells, as well as the increased peripheral oxidative stress levels assessed by L-012-enhanced chemiluminescence were not attenuated by telmisartan treatment of K14-IL-17Aind/+ mice, nor was the persisting skin inflammation. Conclusion: We provide first evidence for an effective antihypertensive treatment in experimental psoriasis by AT1 blockade, but without any impact on vascular inflammation and dysfunction in our mouse model of severe psoriasis-like skin disease. This suggests that vascular function and inflammation in psoriasis might not be attenuated as long as skin inflammation persists.

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