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

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.

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Abstract 348: Inhibition Of Phosphodiesterase 5 Attenuates Angiotensin II-dependent Hypertension And Renal Vascular Dysfunction In C57bl/6 Mice But Not In Enos-Ko Mice

Hypertension ◽

10.1161/hyp.64.suppl_1.348 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Manuel Thieme ◽

Sema Sivritas ◽

Sebastian A Potthoff ◽

Evanthia Mergia ◽

Lars C Rump ◽

...

Keyword(s):

Vascular Function ◽

Vascular Tone ◽

Vascular Dysfunction ◽

Pivotal Role ◽

Ang Ii ◽

Cgmp Signaling ◽

Renal Vascular ◽

The Impact

The kidney plays an outstanding role in the blood pressure (BP) regulation. The renal vasoconstrictor response to angiotensin (Ang) II is balanced by the NO/cGMP-signalling cascade. Ang II causes hypertension and vascular dysfunction by reducing cGMP sensitivity. Ang II is able to increase cGMP degradation by activating phosphodiesterase (PDE)1 and PDE5. The aim of the present study was to identify the predominant PDE subunit regulating renal blood flow (RBF) and vascular tone during hypertension. Therefore, we tested in vivo effects of acute PDE1 (vinpocetine) and PDE5 (sildenafil) inhibition at baseline and during acute Ang II infusion (200ng/kg/min). Furthermore, we examined the impact of PDE-inhibition on Ang II dependent hypertension (500ng/kg/min; 14 days) and on renal vascular function in the isolated perfused kidney. Acute vinpocetine administration (0.8-800μg/kg BW) showed almost no effect on systemic BP and RBF at baseline and during acute Ang II infusion. In contrast, sildenafil (0.8-800μg/kg BW) significantly decreased BP under baseline conditions. During acute Ang II infusion, BP reduction and RBF increase induced by sildenafil was even more pronounced suggesting a pivotal role of the PDE5 in the regulation of renal vascular tone. Based on these results, we tested whether inhibition of the PDE5 protects from hypertension and vascular dysfunction. Indeed, chronic sildenafil treatment significantly attenuated Ang II dependent hypertension in C57BL/6 (vehicle vs. sil: 156±4 vs. 139±7; p<0.05). Moreover, Sildenafil treatment significantly improved NO-dependent vasorelaxation in kidneys of Ang II- treated C57BL/6. To confirm that PDE5 is activated by an increased NO/cGMP signaling, we used eNOS-KO mice, a model known for decreased NO dependent cGMP generation. In eNOS-KO mice, sildenafil failed to reduce Ang II dependent hypertension (172,4 ± 4,3 mmHg vs. 166,1 ± 3,8 mmHg, p=0,2753) and did not improve vascular dysfunction in Ang II treated kidneys. In summary, the PDE5 is the predominant PDE regulating RBF. Inhibition of PDE5 by sildenafil ameliorates chronic Ang II dependent hypertension and improves vascular dysfunction. This study reveals new evidence for the pivotal role of PDE5 in the pathogenesis of AngII-induced hypertension.

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The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

International Journal of Molecular Sciences ◽

10.3390/ijms21239309 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9309

Author(s):

Jessica Maiuolo ◽

Rocco Mollace ◽

Micaela Gliozzi ◽

Vincenzo Musolino ◽

Cristina Carresi ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Endothelial Dysfunction ◽

Blood Vessels ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Vascular Complications ◽

Therapeutic Interventions ◽

The Impact

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20174261 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4261 ◽

Cited By ~ 2

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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Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052366 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2366

Author(s):

Joshua Bond ◽

Tessa Nielsen ◽

Lynette Hodges

Keyword(s):

Chronic Fatigue Syndrome ◽

Vascular Function ◽

Augmentation Index ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Control Group ◽

Fatigue Syndrome ◽

The Impact

Background: Evidence is emerging that individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may suffer from chronic vascular dysfunction as a result of illness-related oxidative stress and vascular inflammation. The study aimed to examine the impact of maximal-intensity aerobic exercise on vascular function 48 and 72 h into recovery. Methods: ME/CFS (n = 11) with gender and age-matched controls (n = 11) were randomly assigned to either a 48 h or 72 h protocol. Each participant had measures of brachial blood pressure, augmentation index (AIx75, standardized to 75 bpm) and carotid-radial pulse wave velocity (crPWV) taken. This was followed by a maximal incremental cycle exercise test. Resting measures were repeated 48 or 72 h later (depending on group allocation). Results: No significant differences were found when ME/CFS were directly compared to controls at baseline. During recovery, the 48 h control group experienced a significant 7.2% reduction in AIx75 from baseline measures (p < 0.05), while the matched ME/CFS experienced no change in AIx75. The 72 h ME/CFS group experienced a non-significant increase of 1.4% from baseline measures. The 48 h and 72 h ME/CFS groups both experienced non-significant improvements in crPWV (0.56 ms−1 and 1.55 ms−1, respectively). Conclusions: The findings suggest that those with ME/CFS may not experience exercise-induced vasodilation due to chronic vascular damage, which may be a contributor to the onset of post-exertional malaise (PEM).

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Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure and Hypertension in Mice and Man

Circulation ◽

10.1161/circulationaha.119.040557 ◽

2020 ◽

Author(s):

Andrii Boguslavskyi ◽

Sergiy Tokar ◽

Oleksandra Prysyazhna ◽

Olena Rudyk ◽

David Sanchez-Tatay ◽

...

Keyword(s):

Blood Pressure ◽

Essential Hypertension ◽

Vascular Function ◽

Vascular Tone ◽

Regional Blood Flow ◽

Hek Cells ◽

The Impact

Background: Background: While it has long been recognized that smooth muscle Na/K ATPase (NKA) modulates vascular tone and blood pressure (BP), the role of its accessory protein phopholemman (PLM) has not been characterized. The aim of this study was to test the hypothesis that PLM phosphorylation regulates vascular tone in vitro and this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in man. Methods: Mouse studies : PLM knock-in mice (PLM 3SA ), in which PLM is rendered unphosphorylatable, were used to assess the role of PLM phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type (WT) and transgenic mice. Human studies : We searched human genomic databases for mutations in PLM in the region of the phosphorylation sites and performed analyses within two human data cohorts (UK Biobank and GoDARTS) to assess the impact of an identified SNP on BP. This SNP was expressed in HEK cells and its effect on PLM phosphorylation determined using Western Blotting. Results: PLM phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of PLM phosphorylation in the PLM 3SA mouse profoundly enhanced vascular responses to PE both in vitro and in vivo . In ageing WT mice PLM was hypophosphorylated and this correlated with the development of ageing-induced essential hypertension. In man we identified a non-synonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in PLM. In HEK cells the R70C mutation prevented PLM phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men. Conclusions: These studies demonstrate the importance of PLM phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for ageing-induced essential hypertension in man.

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B Lymphocyte-Deficiency in Mice Causes Vascular Dysfunction by Inducing Neutrophilia

Biomedicines ◽

10.3390/biomedicines9111686 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1686

Author(s):

Ning Xia ◽

Solveig Hasselwander ◽

Gisela Reifenberg ◽

Alice Habermeier ◽

Ellen I. Closs ◽

...

Keyword(s):

B Cell ◽

B Lymphocytes ◽

Vascular Function ◽

B Lymphocyte ◽

Vascular Dysfunction ◽

Vascular Pathology ◽

Neutrophil Depletion ◽

B Cell Deficiency ◽

Deficient Mice

B lymphocytes have been implicated in the development of insulin resistance, atherosclerosis and certain types of hypertension. In contrast to these studies, which were performed under pathological conditions, the present study provides evidence for the protective effect of B lymphocytes in maintaining vascular homeostasis under physiological conditions. In young mice not exposed to any known risk factors, the lack of B cells led to massive endothelial dysfunction. The vascular dysfunction in B cell-deficient mice was associated with an increased number of neutrophils in the circulating blood. Neutrophil depletion in B cell-deficient mice resulted in the complete normalization of vascular function, indicating a causal role of neutrophilia. Moreover, vascular function in B cell-deficient mice could be restored by adoptive transfer of naive B-1 cells isolated from wild-type mice. Interestingly, B-1 cell transfer also reduced the number of neutrophils in the recipient mice, further supporting the involvement of neutrophils in the vascular pathology caused by B cell-deficiency. In conclusion, we report in the present study the hitherto undescribed role of B lymphocytes in regulating vascular function. B cell dysregulation may represent a crucial mechanism in vascular pathology.

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Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity

Antioxidants ◽

10.3390/antiox10091426 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1426

Author(s):

Néstor de la Visitación ◽

Iñaki Robles-Vera ◽

Javier Moleón ◽

Cristina González-Correa ◽

Nazaret Aguilera-Sánchez ◽

...

Keyword(s):

Blood Pressure ◽

Gut Microbiota ◽

Lupus Erythematosus ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Vascular Complications ◽

Kidney Injury ◽

Interleukin 17 ◽

Toll Like Receptor ◽

Th 17

Our group has investigated the involvement of gut microbiota in hypertension in a murine model of systemic lupus erythematosus induced by Toll-like receptor (TLR)-7 activation. Female BALB/c mice were randomly assigned to four experimental groups: an untreated control (CTR), a group treated with the TLR7 agonist imiquimod (IMQ), IMQ-treated with vancomycin, and IMQ-treated with a cocktail of broad-spectrum antibiotics. We carried out faecal microbiota transplant (FMT) from donor CTR or IMQ mice to recipient IMQ or CTR animals, respectively. Vancomycin inhibited the increase in blood pressure; improved kidney injury, endothelial function, and oxidative stress; and reduced T helper (Th)17 infiltration in aortas from IMQ-treated mice. The rise in blood pressure and vascular complications present in IMQ mice were also observed in the CTR mice recipients of IMQ microbiota. Reduced relative populations of Sutterella and Anaerovibrio were associated with high blood pressure in our animals, which were increased after stool transplantation of healthy microbiota to IMQ mice. The reduced endothelium-dependent vasodilator responses to acetylcholine induced by IMQ microbiota were normalized after interleukin-17 neutralization. In conclusion, gut microbiota plays a role in the TLR7-driven increase in Th17 cell, endothelial dysfunction, vascular inflammation, and hypertension. The vascular changes induced by IMQ microbiota were initiated by Th17 infiltrating the vasculature.

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The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

10.20944/preprints202010.0585.v1 ◽

2020 ◽

Author(s):

Jessica Maiuolo ◽

Rocco Mollace ◽

Micaela Gliozzi ◽

Vincenzo Musolino ◽

Cristina Carresi ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Endothelial Dysfunction ◽

Blood Vessels ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Vascular Complications ◽

Therapeutic Interventions ◽

The Impact

Abstract: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with ACE2 receptor located in endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease leading to irreversible tissue damage and death of patients with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated to the interaction of SARS CoV-2 with ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

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The impact of milk proteins and peptides on blood pressure and vascular function: a review of evidence from human intervention studies

Nutrition Research Reviews ◽

10.1017/s0954422413000139 ◽

2013 ◽

Vol 26 (2) ◽

pp. 177-190 ◽

Cited By ~ 67

Author(s):

Ágnes A. Fekete ◽

D. Ian Givens ◽

Julie A. Lovegrove

Keyword(s):

Blood Pressure ◽

Risk Factor ◽

Whey Protein ◽

Vascular Function ◽

Vascular Dysfunction ◽

Milk Proteins ◽

Vascular Health ◽

Human Trials ◽

The Impact ◽

Proteins And Peptides

CVD are the leading cause of death worldwide. Hypertension, a major controllable risk factor of CVD, is intimately associated with vascular dysfunction, a defect which is also now recognised to be a major, modifiable risk factor for the development of CVD. The purpose of the present review was to critically evaluate the evidence for the effects of milk proteins and their associated peptides on blood pressure (BP) and vascular dysfunction. After a detailed literature search, the number of human trials evaluating the antihypertensive effects of casein-derived peptides (excluding isoleucine-proline-proline and valine-proline-proline) was found to be limited; the studies were preliminary with substantial methodological limitations. Likewise, the data from human trials that examined the effects of whey protein and peptides were also scarce and inconsistent. To date, only one study has conducted a comparative investigation on the relative effects of the two main intact milk proteins on BP and vascular function. While both milk proteins were shown to reduce BP, only whey protein improved measures of arterial stiffness. In contrast, a growing number of human trials have produced evidence to support beneficial effects of both milk proteins and peptides on vascular health. However, comparison of the relative outcomes from these trials is difficult owing to variation in the forms of assessment and measures of vascular function. In conclusion, there is an accumulating body of evidence to support positive effects of milk proteins in improving and/or maintaining cardiovascular health. However, the variable quality of the studies that produced this evidence, and the lack of robust, randomised controlled intervention trials, undermines the formulation of firm conclusions on the potential benefits of milk proteins and peptides on vascular health.

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Abstract P264: Endothelial-specific Interference With PPARγ Activity in Offspring Born From AVP-induced Preeclamptic Pregnancies Has Cardio-renal and Metabolic Consequences

Hypertension ◽

10.1161/hyp.70.suppl_1.p264 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Anand R Nair ◽

Masashi Mukohda ◽

Larry N Agbor ◽

Ko-Ting Lu ◽

Jing Wu ◽

...

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Vascular Dysfunction ◽

Female Offspring ◽

Reduce Blood Pressure ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Hypertensive Disorder ◽

Peroxisome Proliferator Activated Receptor ◽

The Impact

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant-negative (DN) PPARγ driven by an endothelium-specific promoter (E-DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E-DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14-15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular and metabolic function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP-infused pregnancies was similar to mice born to SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine were not different in offspring exposed to PE compared to mice born from SAL pregnancies. However, urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p<0.05) and female (38±3 vs 25±2 mg/ml, p<0.05) adult E-DN born to PE pregnancies compared to E-DN controls born from SAL pregnancies. Male E-DN offspring exposed to PE showed significantly increased gain in body weight over time compared to male NT exposed to PE (ΔBW: 20±8 vs 14±2 g). These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and the adverse renal and metabolic consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for renal and metabolic dysfunction.

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