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Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1–5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55–65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55–65: 2.8 mmHg [95% CI = 1.8–3.7], p 65: 3.7 mmHg [95% CI = 2.7–4.7], p

BACKGROUND: The antifibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT(2)R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via AT(2)R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection via an AT(2)R-dependent mechanism in adult and aged female stroke-prone spontaneously hypertensive rats (SHRSPs). METHODS: In 6-month-old (6MO) and 15-month-old ([15MO]; reproductively senescent) female SHRSP, systolic BP (SBP), GFR, and proteinuria were measured before and after 4 weeks of treatment with vehicle (Veh), RLX (0.5 mg/kg per day s.c.), or RLX+PD123319 (AT(2)R antagonist; 3 mg/kg per day s.c.). Aortic endothelium–dependent relaxation and fibrosis of the kidney, heart, and aorta were assessed. RESULTS: In 6MO SHRSP, RLX significantly enhanced GFR by approximately 25% (P=0.001) and reduced cardiac fibrosis (P=0.01) as compared with vehicle-treated counterparts. These effects were abolished or blunted by PD123319 coadministration. In 15MO females, RLX reduced interstitial renal (P=0.02) and aortic (P=0.003) fibrosis and lowered SBP (13±3 mm Hg; P=0.04) relative to controls. These effects were also blocked by PD123319 cotreatment (all P=0.05 versus RLX treatment alone). RLX also markedly improved vascular function by approximately 40% (P

In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation.

Insulin-regulated aminopeptidase (IRAP), an enzyme that cleaves vasoactive peptides including oxytocin and vasopressin, is suggested to play a role in pregnancy and the onset of preeclampsia. Our aim was to examine the contribution of IRAP to arterial pressure regulation and placental development during pregnancy in mice. Mean arterial pressure and heart rate were measured via radiotelemetry in 12-week-old female wild-type and IRAP knockout mice. Females were time-mated with males of the same genotype. Placentae were collected at embryonic day 18.5 for histological analysis. Basal heart rate was ∼40 bpm lower in IRAP knockout females compared with wild-type females. The increase in heart rate across gestation was greater in IRAP knockout females than wild-type females. Neither basal nor gestational mean arterial pressure was different between wildtype and IRAP knockout females. Urine output and water intake of IRAP knockout mice were ∼45% less than wild-type mice at late gestation. IRAP deficiency had no effect on fetal weight. Morphological assessment of placentae revealed that IRAP deficiency was associated with reduced labyrinth surface area and accumulation of glycogen in the junctional zone. Our data demonstrate that IRAP deficiency alters maternal fluid handling and impairs placental labyrinth expansion at late gestation, indicating that IRAP contributes to the normal adaptions to pregnancy.

BackgroundCardiovascular disease is the leading cause of death in Australia. Investment in research solutions has been demonstrated to yield health and a 9.8-fold return economic benefit. The sector, however, is severely challenged with success rates of traditional peer-reviewed funding in decline. Here, we aimed to understand the perceived challenges faced by the cardiovascular workforce in Australia prior to the COVID-19 pandemic.MethodsWe used an online survey distributed across Australian cardiovascular societies/councils, universities and research institutes over a period of 6 months during 2019, with 548 completed responses. Inclusion criteria included being an Australian resident or an Australian citizen who lived overseas, and a current or past student or employee in the field of cardiovascular research.ResultsThe mean age of respondents was 42±13 years, 47% were male, 85% had a full-time position, and 40% were a group leader or laboratory head. Twenty-three per cent (23%) had permanent employment, and 82% of full-time workers regularly worked >40 hours/week. Sixty-eight per cent (68%) said they had previously considered leaving the cardiovascular research sector. If their position could not be funded in the next few years, a staggering 91% of respondents would leave the sector. Compared to PhD- and age-matched men, women were less likely to be a laboratory head and to feel they had a long-term career path as a cardiovascular researcher, while more women were unsure about future employment and had considered leaving the sector (all pConclusionStrategic solutions, such as diversification of career pathways and funding sources, and moving from a competitive to a collaborative culture, need to be a priority to decrease reliance on government funding and allow cardiovascular researchers to thrive.

Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na+reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na+reabsorption and increased distal Na+delivery and reabsorption. Aldosterone secretion further contributes to distal Na+reabsorption in CKD and is not only mediated by renin and K+but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na+reabsorption. High dietary Na+intake in CKD contributes to Na+retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na+also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na+transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na+channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na+reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na+reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K+or H+binders.

Purpose of review To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. Recent findings Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin–angiotensin–aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease. Summary Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence.

Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI 2 ) and thromboxane (TXA 2 ). Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10mg/kg/day), a PGI 2 analogue (iloprost 100 μg/kg/day), or a dual TXA 2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n=7-8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. SU induced a rapid increase in MAP (16±2 vs. 3±1 mmHg after vehicle on day 6, P2 /TXA 2 ratio in both plasma (2.7±1.2 vs. 0.6±0.2 after vehicle, P=0.05) and urine (22±2.2 vs. 0.9±0.2 after vehicle, P2 /TXA 2 ratio, particularly in the kidney. Although this upregulation might initially be protective, it could eventually contribute to renal toxicity, most likely because PGI 2 exerts deleterious effects in excessive concentrations. Targeting excessive renal PGI 2 production might be another promising strategy to prevent renal toxicity during angiogenesis inhibition.

AimsAlthough effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or anti-hypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria.Methods and resultsMale Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of ∼25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan.ConclusionsOur results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury.

Background The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity. Methods Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified. Findings Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE. Interpretation The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. Fund This study was funded by an mRACE Erasmus MC grant.

Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P P 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.

The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETAR blockade, but not dual ETA/BR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

The New Investigators Committee (NIC) of the International Society of Hypertension (ISH) is a dynamic group of junior doctors and scientists, actively involved in various society activities. This report highlights the events (scientific meetings and summer schools) and activities (social media, mentorship and networking) during 2019 including May Measurement Month and collaborative efforts with the ISH Women in Hypertension Research Committee (WiHRC). The ISH NIC is proud to sponsor awards for outstanding work by junior and emerging researchers at hypertension conferences and also provides opportunities to showcase their work on our social media features such as 'Our Fellows Work' and the New Investigator Spotlight of the month. In 2020, the ISH NIC aims to promote women in leadership roles and to foster strong collaborations with and between society committees and other scientific organizations.

Preeclampsia (PE) is a pregnancy complication, featuring elevated blood pressure and proteinuria, with no appropriate treatment. Activation of the endothelin system has emerged as an important pathway in PE pathophysiology based on experimental PE models where endothelin receptor antagonists (ERAs) prevented or attenuated hypertension and proteinuria. Hence, ERAs have been suggested as potential therapy for PE. However, developmental toxicity studies in animals have shown severe teratogenic effects of ERAs, particularly craniofacial malformations. Nonetheless, sporadic cases of pregnancy in women using ERAs to treat pulmonary hypertension have been described. In this review we give an overview of cases describing ERA use in pregnancy and critically address their possible teratogenic effects. A systematic search in literature yielded 18 articles describing 39 cases with ERA exposure during human pregnancy. In most cases there was only exposure in the first trimester, but exposure later or throughout pregnancy was reported in five cases. Elective termination of pregnancy was performed in 12 pregnancies (31%), two ended in a spontaneous miscarriage (5%) and no fetal congenital abnormalities have been described in the remaining cases. These preliminary findings support the idea that ERA treatment for severe, early onset PE might be an option if applied later in pregnancy, when organogenesis is completed to avoid teratogenic risks. However, third trimester toxicology studies are warranted to evaluate drug safety. Subsequently, it remains to be established whether ERA treatment is effective for alleviating maternal symptoms, as demonstrated in preclinical PE models, allowing pregnancy prolongation without leading to adverse neonatal outcomes.

Adequate development of the placenta is essential for optimal pregnancy outcome. Pre-eclampsia (PE) is increasingly recognized to be a consequence of placental dysfunction and can cause serious maternal and fetal complications during pregnancy. Furthermore, PE increases the risk of neonatal problems and has been shown to be a risk factor for cardiovascular disease of the mother later in life. Currently, there is no adequate treatment for PE, mainly because its multifactorial pathophysiology remains incompletely understood. It originates in early pregnancy with abnormal placentation and involves a cascade of dysregulated systems in the placental vasculature. To investigate therapeutic strategies it is essential to understand the regulation of vascular reactivity and remodeling of blood vessels in the placenta. Techniques using human tissue such as the ex vivo placental perfusion model provide insight in the vasoactive profile of the placenta, and are essential to study the effects of drugs on the fetal vasculature. This approach highlights the different pathways that are involved in the vascular regulation of the human placenta, changes that occur during PE and the importance of focusing on restoring these dysfunctional systems when studying treatment strategies for PE.

In a recent issue of Clinical Science, Stanhewicz et al. investigated persistent microvascular dysfunction in women up to 16 months postpartum. The authors found sensitivity to the pressor effects of endothelin-1 (ET-1) was enhanced when compared with women who had a normotensive pregnancy. Importantly, the authors demonstrated that this effect was mediated via the endothelin type B (ETB) receptors. Therefore, the present study highlights the possibility that alterations in the localization of the ETB receptor contributes to the pathogenesis of pre-eclampsia and future cardiovascular disease (CVD) risk. Currently, there is great interest in the role of the endothelin system in pre-eclampsia. Targetting the endothelin system, potentially by modulating upstream pathways to prevent ETB receptor dysfunction, may improve health outcomes for women and their offspring during pre-eclampsia and later life.

BACKGROUND: Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT(2)R) to ameliorate renal fibrogenesis in vitro and in vivo. Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT(1)R), which is expressed on myofibroblasts along with RXFP1 and AT(2)R, is unknown. METHODS: We examined the signal transduction mechanisms of serelaxin when applied to primary rat renal and human cardiac myofibroblasts in vitro, and in three models of renal- or cardiomyopathy-induced fibrosis in vivo. RESULTS: The AT(1)R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo. Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system that serelaxin did not directly bind to AT(1)Rs but that constitutive AT(1)R–RXFP1 interactions could form. To potentially explain these findings, we also demonstrated that renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an AT(2)R agonist (compound 21). CONCLUSIONS: These findings have significant implications for the concomitant use of RXFP1 or AT(2)R agonists with AT(1)R blockers, and suggest that functional interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.

A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and sustained antihypertensive effect, lasting weeks to months in preclinical models. It is not known whether conventional vasopressors are effective to reverse RNAi-mediated blood pressure lowering. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion. Spontaneously hypertensive rats on a low-salt diet (

Since the 1970s, we have known that aspirin can reduce the risk of pre‐eclampsia. However, the underlying mechanisms explaining this risk reduction are poorly understood. Both cyclooxygenase (COX)‐1‐ and COX‐2‐dependent effects might be involved. As a consequence of this knowledge hiatus, the optimal dose and timing of initiation of aspirin therapy are not clear. Here, we review how (COX‐1 versus COX‐2 inhibition) and when (prevention versus treatment) aspirin therapy may interfere with the mechanisms implicated in the pathogenesis of pre‐eclampsia. The available evidence suggests that both COX‐1‐ and COX‐2‐dependent effects play important roles in the early stage of aberrant placental development and in the next phase leading to the clinical syndrome of pre‐eclampsia. Collectively, these data suggest that high‐dose (dual COX inhibition) aspirin may be superior to standard low‐dose (selective COX‐1 inhibition) aspirin for the prevention and also treatment of pre‐eclampsia. Therefore, we conclude that more functional and biochemical tests are needed to unravel the contribution of prostanoids in the mechanisms implicated in the pathogenesis of pre‐eclampsia and the potential of dual COX and/or selective COX‐2 inhibition for the prevention and treatment of pre‐eclampsia. This information is vital if we are to deduce the suitability, optimal timing and dose of aspirin and/or a specific COX‐2 inhibitor (most likely using modified forms that do not cross the placenta) that can then be tested in a randomized, controlled trial instead of the current practice of empirical dosing regimens.

Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt ) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (−68±4 mm Hg), followed by captopril+valsartan (−54±4 mm Hg), captopril (−23±2 mm Hg), siRNA (−14±2 mm Hg), and valsartan (−10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K + increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.

The renin–angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1–7) [Ang(1–7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life.

The renin–angiotensin system is one of the key long-term regulators of blood pressure and has been a mainstay for the treatment of cardiovascular and renal diseases for the last 30 years. In recent years, new components of the renin–angiotensin system have been discovered beyond the classical pathway that have led to the development of novel therapies targeting this system. Moreover, dual inhibitors which block the renin–angiotensin system and other systems involved in the regulation of blood pressure may provide superior treatment for cardiovascular and renal diseases.

Since the formation of new blood vessels is essential for tumour growth and metastatic spread, inhibition of angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway is an effective strategy for various types of cancer, most importantly renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. However, VEGF inhibitors have serious side effects, most importantly hypertension and nephropathy. In case of fulminant hypertension, this may only be handled by lowering the dosage since the blood pressure rise is proportional to the amount of VEGF inhibition. These effects pathophysiologically and clinically resemble the most severe complication of pregnancy, preeclampsia, in which case an insufficient placenta leads to a rise in sFlt-1 levels causing a decrease in VEGF availability. Due to this overlap, studies in preeclampsia may provide important information for VEGF inhibitor-induced toxicity and vice versa. In both VEGF inhibitor-induced toxicity and preeclampsia, endothelin (ET)-1 appears to be a pivotal player. In this review, after briefly summarizing the anticancer effects, we discuss the mechanisms that potentially underlie the unwanted effects of VEGF inhibitors, focusing on ET-1, nitric oxide and oxidative stress, the renin-angiotensin-aldosterone system, and rarefaction. Given the salt sensitivity of this phenomenon, as well as the beneficial effects of aspirin in preeclampsia and cancer, we next provide novel treatment options for VEGF inhibitor-induced toxicity, including salt restriction, ET receptor blockade, and cyclo-oxygenase inhibition, in addition to classical antihypertensive and renoprotective drugs. We conclude with the recommendation of therapeutic drug monitoring to improve patient outcome.

Preeclampsia (PE) is a serious pregnancy complication characterized by suboptimal placentation, leading to increased vascular resistance and generalized endothelial dysfunction. A promising treatment is sildenafil, a phosphodiesterase-5 (PDE5) inhibitor that enhances nitric oxide (NO) mediated vasodilation. Although there are currently sildenafil trials ongoing in pregnant women, the effects of sildenafil on the placenta are still unknown. Placentas of healthy (n=17), early-onset (Eo)PE (n=6) and late-onset (Lo)PE (n=5) pregnancies were dually perfused, pre-constricted with serotonin, and subsequently exposed to the NO donor SNP in the absence or presence of 1 μmol/L sildenafil. Two healthy placentas were perfused with sildenafil on the maternal side to study placental transfer. Placental protein expression of PDE5, PDE1A, eNOS and iNOS was assessed using Western blot. Mean baseline pressure ±SEM was significantly lower (p-6 M SNP in healthy (mean pressure decrease 4.3±0.8 vs. 8.1±1.9 mmHg, p=0.1) and LoPE placentas (3.0±1.0 vs. 7.3±3.2 mmHg), while no improvement was seen in EoPE placentas (6.0±2.0 vs. 5.0±1.0 mmHg). When sildenafil was added at the maternal side, average fetal-maternal concentration ratio was 0.22 after 3 hours of perfusion, as compared to 0.86 for antipyrine, a freely diffusing molecule. Placental levels of PDE1A tended to be higher in PE (p=0.08), while no differences in expression of PDE5, eNOS and iNOS were observed between PE and healthy placentas. Our study reveals that PE placentas have a significantly lower baseline pressure compared to healthy placentas, possibly due to lower resistance in the feto-placental vasculature as a compensation mechanism for the increased resistance in the spiral arteries. Although sildenafil tended to enhance vasodilation in healthy and LoPE placentas, it did not have those beneficial effects in EoPE. Possibly PDE1A-selective inhibitors should be applied in PE, or PDE is not the appropriate target for restoring disturbed vasodilation.

Angiotensinogen (AGT) synthesis is proposed to occur not only in the liver, but also in kidney, brain and adipocytes. Selectively deleting hepatic AGT might therefore not affect renal angiotensin (Ang) levels. Here we investigated whether arterial pressure lowering with liver-targeted AGT siRNA versus renin-Ang system (RAS) blockers affects renal function and Ang levels. Arterial pressure was measured via radiotelemetry in spontaneously hypertensive rats during vehicle, valsartan, captopril (both p.o.), siRNA (s.c. fortnightly injection), siRNA+valsartan or captopril+valsartan treatment for 4 weeks. Transcutaneous measurement of glomerular filtration rate (GFR) and 24h urinary excretory function was assessed at 2 and 4 weeks. Renal Ang levels were measured by mass spectrometry. Dual RAS blockade synergistically lowered arterial pressure compared to monotherapy. Valsartan and captopril increased AngI (1096±205 and 939±128 fmol/g, respectively versus 413±46 fmol/g in vehicle-treated; both P70% after valsartan, captopril and captopril+valsartan (all P1 R may allow renal AngII to remain intact after AGT siRNA, and only dual RAS blockade significantly reduces renal AngII. AGT siRNA synergistically lowers arterial pressure when combined with existing RAS blockers and may be a novel treatment for hypertension without apparent negative effects on renal function.

All angiotensin stems from angiotensinogen (AGT). A single dose of small interfering ribonucleic acids (siRNA) targeting AGT may provide long-lasting blood pressure reductions, as it would abolish angiotensin generation. Here we assessed efficacy of AGT siRNA in spontaneously hypertensive rats (SHRs). SHRs were treated for 4 weeks with vehicle, siRNA (10 mg/kg; s.c. every 2 weeks), valsartan (31 mg/kg/day; oral), captopril (100 mg/kg/day; oral), valsartan+siRNA, or captopril+valsartan (all groups n=8). Mean arterial pressure (MAP) was measured via radiotelemetry. Baseline MAP was 137±2 mmHg. ΔMAP was largest after valsartan+siRNA (-67±3 mmHg; P+ tended to increase in all groups, significance being reached only in the valsartan+siRNA group. Both types of dual blockade attenuated normal growth from the second week of treatment onwards. In conclusion, due to renin upregulation, circulating angiotensin II remained intact even with only 1.4% of AGT left, relative to pretreatment. Consequently, AGT siRNA caused a similar antihypertensive effect as valsartan and captopril. Importantly, when combining siRNA+valsartan, angiotensin II collapsed, and blood pressure decreased synergistically. Given the potential for low dosing frequency suggested by this study, this novel treatment may address medication adherence problems in patients with resistant hypertension and further development is warranted.

Vascular endothelial growth factor inhibitor (VEGFi)-induced hypertension and renal injury in cancer patients mimic the clinical phenotype of preeclampsia. ET-1 has been implicated to be involved. Since aspirin can prevent the onset of preeclampsia, we hypothesized that co-treatment of the VEGFi sunitinib (SU) with aspirin might be beneficial and may improve ET-1 status. Male WKY rats were treated with vehicle, 14 mg/kg/day SU, or SU + low or high dose aspirin (5 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry. On day 8, 24h urine was collected to determine albuminuria and prostanoid (PGF2α and TxB2) levels. Plasma endothelin-1 (ET-1) was measured via ELISA. Endothelial dysfunction was assessed in iliac vessels and reactive oxygen species (ROS) was measured via aortic superoxide anion production. Renal cyclooxygenase (COX)-1, COX-2 and ET-1 mRNA expression were determined via PCR. SU induced a rapid and sustained increase in MAP (24±2 versus 1±1 mmHg in vehicle on day 6; P

The angiotensin type 2 receptor (AT 2 R) mediates cardiovascular and renal protection in females of reproductive age, a mechanism that is lost with advancing age. Recently, we demonstrated that the nitric oxide-promoting and transforming growth factor-β1 inhibitory actions of relaxin (RLX) involve an interaction between the relaxin-insulin like family peptide receptor 1 (RXFP1) and the AT 2 R. In the present study, we aimed to determine whether RLX induces cardio-renal protection and slows the progression of end-organ damage, via an AT 2 R-dependent mechanism. In female stroke prone-spontaneously hypertensive rats (SP-SHR) at 6 (young) and 14-15 (aged reproductively senescent) months of age arterial pressure, cardiac function, glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks of treatment with vehicle (sodium acetate s.c.), RLX (serelaxin; 0.5mg/kg/day s.c.) or RLX+PD123319 (AT 2 R antagonist; 3mg/kg/day s.c). In addition, aortic endothelium-dependent relaxation in response to acetylcholine was assessed and cardiac and renal tissues were histologically analyzed for fibrosis. An age-related decline in GFR and increases in arterial pressure, proteinuria and cardiac and renal fibrosis were observed (all P2 R. Thus, targeting the RXFP1-AT 2 R axis may be a therapeutic option for the treatment of cardiovascular disease and associated end-organ damage in hypertensive women.

The authors present sexual dimorphism at the molecular, cellular and tissue level and suggest that it contributes to differences in disease onset, susceptibility, prevalence and treatment responses in hypertension and cardiovascular disease. Several factors that confer relative cardioprotection in women are discussed, including biological age, sex hormones, sex chromosome complement and lifestyle. Although intrinsic mechanisms that regulate arterial blood pressure (BP) are similar in men and women, marked variations exist at the molecular, cellular and tissue levels. These physiological disparities between the sexes likely contribute to differences in disease onset, susceptibility, prevalence and treatment responses. Key systems that are important in the development of hypertension and cardiovascular disease (CVD), including the sympathetic nervous system, the renin–angiotensin–aldosterone system and the immune system, are differentially activated in males and females. Biological age also contributes to sexual dimorphism, as premenopausal women experience a higher degree of cardioprotection than men of similar age. Furthermore, sex hormones such as oestrogen and testosterone as well as sex chromosome complement likely contribute to sex differences in BP and CVD. At the cellular level, differences in cell senescence pathways may contribute to increased longevity in women and may also limit organ damage caused by hypertension. In addition, many lifestyle and environmental factors — such as smoking, alcohol consumption and diet — may influence BP and CVD in a sex-specific manner. Evidence suggests that cardioprotection in women is lost under conditions of obesity and type 2 diabetes mellitus. Treatment strategies for hypertension and CVD that are tailored according to sex could lead to improved outcomes for affected patients.

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment of cardiovascular and renal diseases. Angiotensin II and aldosterone are the two most powerful biologically active products of the RAAS, inducing all of the classical actions of the RAAS including vasoconstriction, sodium retention, tissue remodeling and pro-inflammatory and pro-fibrotic effects. In recent years, new components of the RAAS have been discovered beyond the classical pathway that have led to the identification of depressor or so-called protective RAAS pathways and the development of novel therapies targeting this system. Moreover, dual inhibitors which block the RAAS and other systems involved in the regulation of blood pressure or targeting upstream of angiotensin II by selectively deleting liver-derived angiotensinogen, the precursor to all angiotensins, may provide superior treatment for cardiovascular and renal diseases and revolutionize RAAS-targeting therapy.

Background Animal models have become valuable experimental tools for understanding the pathophysiology and therapeutic interventions in cardiovascular disease. Yet to date, few studies document the age- and sex-related differences in arterial pressure, circadian rhythm, and renal function in normotensive mice under basal conditions, across the life span. We hypothesized that mice display similar sex- and age-related differences in arterial pressure and renal function to humans. Methods Mean arterial pressure (MAP) and circadian rhythm of arterial pressure were measured over 3 days via radiotelemetry, in 3- and 5-month-old (adult) and 14- and 18-month-old (aged) FVB/N and in 5-month-old (adult) C57BL/6 male and female normotensive mice. In FVB/N mice, albuminuria from 24-h urine samples as well as body, heart, and kidney weights were measured at each age. Results Twenty-four-hour MAP was greater in males than females at 3, 5, and 14 months of age. A similar sex difference in arterial pressure was observed in C57BL/6 mice at 5 months of age. In FVB/N mice, 24-h MAP increased with age, with females displaying a greater increase between 3 and 18 months of age than males, such that MAP was no longer different between the sexes at 18 months of age. A circadian pattern was observed in arterial pressure, heart rate, and locomotor activity, with values for each greater during the active (night/dark) than the inactive (day/light) period. The night-day dip in MAP was greater in males and increased with age in both sexes. Albuminuria was greater in males than females, increased with age in both sexes, and rose to a greater level in males than females at 18 months of age. Conclusions Arterial pressure and albuminuria increase in an age- and sex-specific manner in mice, similar to patterns observed in humans. Thus, mice represent a useful model for studying age and sex differences in the regulation of arterial pressure and renal disease. Understanding the mechanisms that underlie the pathophysiology of cardiovascular disease may lead to new and better-tailored therapies for men and women.

Epidemiological evidence links recurrent dehydration associated with periodic water intake with chronic kidney disease (CKD). However, minimal attention has been paid to the long-term impact of periodic water intake on the progression of CKD and underlying mechanisms involved. Therefore we investigated the chronic effects of recurrent dehydration associated with periodic water restriction on arterial pressure and kidney function and morphology in male spontaneously hypertensive rats (SHR). Arterial pressure increased and glomerular filtration rate decreased in water-restricted SHR. This was observed in association with cyclic changes in urine osmolarity, indicative of recurrent dehydration. Additionally, water-restricted SHR demonstrated greater renal fibrosis and an imbalance in favour of pro-inflammatory cytokine-producing renal T cells compared to their control counterparts. Furthermore, urinary NGAL levels were greater in water-restricted than control SHR. Taken together, our results provide significant evidence that recurrent dehydration associated with chronic periodic drinking hastens the progression of CKD and hypertension, and suggest a potential role for repetitive bouts of acute renal injury driving renal inflammatory processes in this setting. Further studies are required to elucidate the specific pathways that drive the progression of recurrent dehydration-induced kidney disease.