Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue.

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.

Metacognitive therapy home-based self-help for anxiety and depression in cardiovascular disease patients in the UK: A single-blind randomised controlled trial.

BACKGROUND: Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT). METHODS AND FINDINGS: We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR (n = 118, 49.2%) or usual CR alone (n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = -2.64 [-4.49 to -0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data. CONCLUSION: Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients. TRIAL REGISTRATION: NCT03999359.

Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation: PATHWAY-A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy.

BACKGROUND: Depression and anxiety in cardiovascular disease are significant, contributing to poor prognosis. Unfortunately, current psychological treatments offer mixed, usually small improvements in these symptoms. The present trial tested for the first time the effects of group metacognitive therapy (MCT; 6 sessions) on anxiety and depressive symptoms when delivered alongside cardiac rehabilitation (CR). METHODS: A total of 332 CR patients recruited from 5 National Health Service Trusts across the North-West of England were randomly allocated to MCT+CR (n=163, 49.1%) or usual CR alone (n=169, 50.9%). Randomization was 1:1 via minimization balancing arms on sex and Hospital Anxiety and Depression Scale scores within hospital site. The primary outcome was Hospital Anxiety and Depression Scale total after treatment (4-month follow-up). Secondary outcomes were individual Hospital Anxiety and Depression Scales, traumatic stress symptoms, and psychological mechanisms including metacognitive beliefs and repetitive negative thinking. Analysis was intention to treat. RESULTS: The adjusted group difference on the primary outcome, Hospital Anxiety and Depression Scale total score at 4 months, significantly favored the MCT+CR arm (-3.24 [95% CI, -4.67 to -1.81], P<0.001; standardized effect size, 0.52 [95% CI, 0.291 to 0.750]). The significant difference was maintained at 12 months (-2.19 [95% CI, -3.72 to -0.66], P=0.005; standardized effect size, 0.33 [95% CI, 0.101 to 0.568]). The intervention improved outcomes significantly for both depression and anxiety symptoms when assessed separately compared with usual care. Sensitivity analysis using multiple imputation of missing values supported these findings. Most secondary outcomes favored MCT+CR, with medium to high effect sizes for psychological mechanisms of metacognitive beliefs and repetitive negative thinking. No adverse treatment-related events were reported. CONCLUSIONS: Group MCT+CR significantly improved depression and anxiety compared with usual care and led to greater reductions in unhelpful metacognitions and repetitive negative thinking. Most gains remained significant at 12 months. Study strengths include a large sample, a theory-based intervention, use of longer-term follow-up, broad inclusion criteria, and involvement of a trials unit. Limitations include no control for additional contact as part of MCT to estimate nonspecific effects, and the trial was not intended to assess cardiac outcomes. Nonetheless, results demonstrated that addition of the MCT intervention had broad and significant beneficial effects on mental health symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ISRCTN74643496.

Perivascular Adipose Tissue Anticontractile Function Is Mediated by Both Endothelial and Neuronal Nitric Oxide Synthase Isoforms.

BACKGROUND: The mechanism of the perivascular adipose tissue (PVAT) anticontractile effect is well characterized in rodent visceral vascular beds; however, little is known about the mechanism of PVAT anticontractile function in subcutaneous vessels. In addition, we have previously shown that PVAT anticontractile function is nitric oxide synthase (NOS) dependent but have not investigated the roles of NOS isoforms. OBJECTIVE: Here, we examined PVAT anticontractile function in the mouse gracilis artery, a subcutaneous fat depot, in lean control and obese mice and investigated the mechanism in comparison to a visceral depot. METHOD: Using the wire myograph, we generated responses to noradrenaline and electrical field stimulation in the presence of pharmacological tools targeting components of the known PVAT anticontractile mechanism. In addition, we performed ex vivo "fat transplants" in the organ bath. RESULTS: The mechanism of PVAT anticontractile function is similar between subcutaneous and visceral PVAT depots. Both endothelial and neuronal NOS isoforms mediated the PVAT anticontractile effect. Loss of PVAT anticontractile function in obesity is independent of impaired vasoreactivity, and function can be restored in visceral PVAT by NOS activation. CONCLUSIONS: Targeting NOS isoforms may be useful in restoring PVAT anticontractile function in obesity, ameliorating increased vascular tone, and disease.

Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise.

PURPOSE: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and ß3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function. METHODS: Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of ß3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT. RESULTS: High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via ß3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing ß3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored. CONCLUSION: Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Interleukin-33 rescues perivascular adipose tissue anticontractile function in obesity.

Perivascular adipose tissue (PVAT) depots are metabolically active and play a major vasodilator role in healthy lean individuals. In obesity, they become inflamed and eosinophil-depleted and the anticontractile function is lost with the development of diabetes and hypertension. Moreover, eosinophil-deficient ΔdblGATA-1 mice lack PVAT anticontractile function and exhibit hypertension. Here, we have investigated the effects of inducing eosinophilia on PVAT function in health and obesity. Control, obese, and ΔdblGATA-1 mice were administered intraperitoneal injections of interleukin-33 (IL-33) for 5 days. Conscious restrained blood pressure was measured, and blood was collected for glucose and plasma measurements. Wire myography was used to assess the contractility of mesenteric resistance arteries. IL-33 injections induced a hypereosinophilic phenotype. Obese animals had significant elevations in blood pressure, blood glucose, and plasma insulin, which were normalized with IL-33. Blood glucose and insulin levels were also lowered in lean treated mice. In arteries from control mice, PVAT exerted an anticontractile effect on the vessels, which was enhanced with IL-33 treatment. In obese mice, loss of PVAT anticontractile function was rescued by IL-33. Exogenous application of IL-33 to isolated arteries induced a rapidly decaying endothelium-dependent vasodilation. The therapeutic effects were not seen in IL-33-treated ΔdblGATA-1 mice, thereby confirming that the eosinophil is crucial. In conclusion, IL-33 treatment restored PVAT anticontractile function in obesity and reversed development of hypertension, hyperglycemia, and hyperinsulinemia. These data suggest that targeting eosinophil numbers in PVAT offers a novel approach to the treatment of hypertension and type 2 diabetes in obesity.NEW & NOTEWORTHY In this study, we have shown that administering IL-33 to obese mice will restore PVAT anticontractile function, and this is accompanied by normalized blood pressure, blood glucose, and plasma insulin. Moreover, the PVAT effect is enhanced in control mice given IL-33. IL-33 induced a hypereosinophilic phenotype in our mice, and the effects of IL-33 on PVAT function, blood pressure, and blood glucose are absent in eosinophil-deficient mice, suggesting that the effects of IL-33 are mediated via eosinophils.

Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo.

BACKGROUND: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte ß3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of ß3-adrenoceptors and adiponectin. METHOD: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using ß3-adrenoceptor inhibition, and activation of ß3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The ß3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon ß3-adrenoceptor activation. CONCLUSIONS: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte ß3-adrenoceptors, which may trigger release of the vasodilator adiponectin.

Role of Sympathetic Nerves and Adipocyte Catecholamine Uptake in the Vasorelaxant Function of Perivascular Adipose Tissue.

OBJECTIVE: Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on resistance arteries which is vital in regulating arterial tone. Activation of ß3-adrenoceptors by sympathetic nerve-derived NA (noradrenaline) may be implicated in this effect and may stimulate the release of the vasodilator adiponectin from adipocytes. Understanding the mechanisms responsible is vital for determining how PVAT may modify vascular resistance in vivo. APPROACH AND RESULTS: Electrical field stimulation profiles of healthy C57BL/6J mouse mesenteric resistance arteries were characterized using wire myography. During electrical field stimulation, PVAT elicits a reproducible anticontractile effect, which is endothelium independent. To demonstrate the release of an anticontractile factor, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT-denuded vessel. Post-transfer contractility was significantly reduced confirming that stimulated PVAT releases a transferable anticontractile factor. Sympathetic denervation of PVAT using tetrodotoxin or 6-hydroxydopamine completely abolished the anticontractile effect. ß3-adrenoceptor antagonist SR59203A reduced the anticontractile effect, although the PVAT remained overall anticontractile. When the antagonist was used in combination with an OCT3 (organic cation transporter 3) inhibitor, corticosterone, the anticontractile effect was completely abolished. Application of an adiponectin receptor-1 blocking peptide significantly reduced the anticontractile effect in +PVAT arteries. When used in combination with the ß3-adrenoceptor antagonist, there was no further reduction. In adiponectin knockout mice, the anticontractile effect is absent. CONCLUSIONS: The roles of PVAT are 2-fold. First, sympathetic stimulation in PVAT triggers the release of adiponectin via ß3-adrenoceptor activation. Second, PVAT acts as a reservoir for NA, preventing it from reaching the vessel and causing contraction.

Emerging Roles of Sympathetic Nerves and Inflammation in Perivascular Adipose Tissue.

Perivascular adipose tissue (PVAT) is no longer recognised as simply a structural support for the vasculature, and we now know that PVAT releases vasoactive factors which modulate vascular function. Since the discovery of this function in 1991, PVAT research is rapidly growing and the importance of PVAT function in disease is becoming increasingly clear. Obesity is associated with a plethora of vascular conditions; therefore, the study of adipocytes and their effects on the vasculature is vital. PVAT contains an adrenergic system including nerves, adrenoceptors and transporters. In obesity, the autonomic nervous system is dysfunctional; therefore, sympathetic innervation of PVAT may be the key mechanistic link between increased adiposity and vascular disease. In addition, not all obese people develop vascular disease, but a common feature amongst those that do appears to be the inflammatory cell population in PVAT. This review will discuss what is known about sympathetic innervation of PVAT, and the links between nerve activation and inflammation in obesity. In addition, we will examine the therapeutic potential of exercise in sympathetic stimulation of adipose tissue.

May Measurement Month 2017: an analysis of blood pressure screening results from the United Kingdom and the Republic of Ireland-Europe.

Elevated blood pressure (BP), or hypertension, is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and acting as a stimulus to improving screening programmes worldwide. In the United Kingdom (UK) nearly 1 in 5 people, and in the Republic of Ireland (RoI) 3 out of 10, have hypertension, of which a large proportion remains undiagnosed. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed a standardized protocol. Screenings sites in hospitals, universities, shopping centres, workplaces, sports clubs, community centres, GP practices, and pharmacies were set up across the UK and RoI as part of this initiative. Seven thousand seven hundred and fourteen individuals were screened during MMM17. After multiple imputation, 3099 (40.3%) had hypertension. Of individuals not receiving antihypertensive medication, 1406 (23.4%) were hypertensive. Of individuals receiving antihypertensive medication, 682 (40.5%) had uncontrolled BP. MMM17 was the largest BP screening campaign ever undertaken in the UK and RoI. These data prove for the first time that a relatively inexpensive, volunteer based, convenience sampling of screening BP in the community identified two out of five individuals as hypertensive, with one in four not receiving treatment. Of major concern is that these data demonstrate that of those individuals receiving treatment, two out of five still did not have controlled BP.

A randomized controlled crossover trial evaluating differential responses to antihypertensive drugs (used as mono- or dual therapy) on the basis of ethnicity: The comparIsoN oF Optimal Hypertension RegiMens; part of the Ancestry Informative Markers in HYpertension program-AIM-HY INFORM trial.

BACKGROUND: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a "black versus white" approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia. STUDY DESIGN: The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure. CONCLUSION: AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations.

Modulation of Vascular Reactivity by Perivascular Adipose Tissue (PVAT).

PURPOSE OF REVIEW: In this review, we discuss the role of perivascular adipose tissue (PVAT) in the modulation of vascular contractility and arterial pressure, focusing on the role of the renin-angiotensin-aldosterone system and oxidative stress/inflammation. RECENT FINDINGS: PVAT possesses a relevant endocrine-paracrine activity, which may be altered in several pathophysiological and clinical conditions. During the last two decades, it has been shown that PVAT may modulate vascular reactivity. It has also been previously demonstrated that inflammation in adipose tissue may be implicated in vascular dysfunction. In particular, adipocytes secrete a number of adipokines with various functions, as well as several vasoactive factors, together with components of the renin-angiotensin system which may act at local or at systemic level. It has been shown that the anti-contractile effect of PVAT is lost in obesity, probably as a consequence of the development of adipocyte hypertrophy, inflammation, and oxidative stress. Adipose tissue dysfunction is interrelated with inflammation and oxidative stress, thus contributing to endothelial dysfunction observed in several pathological and clinical conditions such as obesity and hypertension. Decreased local adiponectin level, macrophage recruitment and infiltration, and activation of renin-angiotensin-aldosterone system could play an important role in this regard.

Obesity-Related Perivascular Adipose Tissue Damage Is Reversed by Sustained Weight Loss in the Rat.

OBJECTIVE: Perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists, and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been characterized after weight loss induced by caloric restriction, which is often the first line treatment for obesity. APPROACH AND RESULTS: Contractility studies were performed using wire myography on small mesenteric arteries with and without PVAT from control, diet-induced obese, calorie restricted and sustained weight loss rats. Changes in the PVAT environment were assessed using immunohistochemistry. PVAT from healthy animals elicited an anticontractile effect in response to norepinephrine. This was abolished in diet-induced obesity through a mechanism involving increased local tumor necrosis factor-α and reduced nitric oxide bioavailability within PVAT. Sustained weight loss led to improvement in PVAT function associated with restoration of adipocyte size, reduced tumor necrosis factor-α, and increased nitric oxide synthase function. This was associated with reversal of obesity-induced hypertension and normalization of plasma adipokine levels, including leptin and insulin. CONCLUSIONS: We have shown that diet-induced weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and increased nitric oxide synthase activity within PVAT. These data reveal inflammation and nitric oxide synthase, particularly endothelial nitric oxide synthase, as potential targets for the treatment of PVAT dysfunction associated with obesity and metabolic syndrome.

Effects of Obesity on Perivascular Adipose Tissue Vasorelaxant Function: Nitric Oxide, Inflammation and Elevated Systemic Blood Pressure.

INTRODUCTION: Perivascular adipose tissue (PVAT) surrounds most vessels in the human body. Healthy PVAT has a vasorelaxant effect which is not observed in obesity. We assessed the contribution of nitric oxide (NO), inflammation and endothelium to obesity-induced PVAT damage. METHODS: Rats were fed a high-fat diet or normal chow. PVAT function was assessed using wire myography. Skeletonised and PVAT-intact mesenteric vessels were prepared with and without endothelium. Vessels were incubated with L-NNA or superoxide dismutase (SOD) and catalase. Gluteal fat biopsies were performed on 10 obese and 10 control individuals, and adipose tissue was assessed using proteomic analysis. RESULTS: In the animals, there were significant correlations between weight and blood pressure (BP; r = 0.5, p = 0.02), weight and PVAT function (r = 0.51, p = 0.02), and PVAT function and BP (r = 0.53, p = 0.01). PVAT-intact vessel segments from healthy animals constricted significantly less than segments from obese animals (p < 0.05). In a healthy state, there was preservation of the PVAT vasorelaxant function after endothelium removal (p < 0.05). In endothelium-denuded vessels, L-NNA attenuated the PVAT vasorelaxant function in control vessels (p < 0.0001). In obesity, incubation with SOD and catalase attenuated PVAT-intact vessel contractility in the presence and absence of endothelium (p < 0.001). In obese humans, SOD [Cu-Zn] (SOD1; fold change -2.4), peroxiredoxin-1 (fold change -2.15) and adiponectin (fold change -2.1) were present in lower abundances than in healthy controls. CONCLUSIONS: Incubation with SOD and catalase restores PVAT vasorelaxant function in animal obesity. In the rodent model, obesity-induced PVAT damage is independent of endothelium and is in part due to reduced NO bioavailability within PVAT. Loss of PVAT function correlates with rising BP in our animal obesity model. In keeping with our hypothesis of inflammation-induced damage to PVAT function in obesity, there are lower levels of SOD1, peroxiredoxin-1 and adiponectin in obese human PVAT.

Mechanisms of adiponectin-associated perivascular function in vascular disease.

The concept that fat cells could influence the circulation and indeed cardiac function has been in existence for ≥20 years and has gained a wide interest and no less excitement as evidence has accrued to suggest that such effects may be profound enough to explain disease states, such as hypertension and metabolic changes associated with obesity and type II diabetes mellitus. This ATVB in Focus intends to examine our current knowledge in this field, and suggests mechanisms that may be responsible for normal perivascular function and how they become disordered in obesity. There is the tantalizing prospect of developing new therapeutic approaches to keep obese individuals healthy and redesignating type II diabetes mellitus as a vascular disease.

ß Integrins mediate FAK Y397 autophosphorylation of resistance arteries during eutrophic inward remodeling in hypertension.

Human essential hypertension is characterized by eutrophic inward remodeling of the resistance arteries with little evidence of hypertrophy. Upregulation of αVß3 integrin is crucial during this process. In order to investigate the role of focal adhesion kinase (FAK) activation in this process, the level of FAK Y397 autophosphorylation was studied in small blood vessels from young TGR(mRen2)27 animals as blood pressure rose and eutrophic inward remodeling took place. Between weeks 4 and 5, this process was completed and accompanied by a significant increase in FAK phosphorylation compared with normotensive control animals. Phosphorylated (p)FAK Y397 was coimmunoprecipitated with both ß1- and ß3-integrin-specific antibodies. In contrast, only a fraction (<10-fold) was coprecipitated with the ß3 integrin subunit in control vessels. Inhibition of eutrophic remodeling by cRGDfV treatment of TGR(mRen2)27 rats resulted in the development of smooth-muscle-cell hypertrophy and a significant further enhancement of FAK Y397 phosphorylation, but this time with exclusive coassociation of pFAK Y397 with integrin ß1. We established that phosphorylation of FAK Y397 with association with ß1 and ß3 integrins occurs with pressure-induced eutrophic remodeling. Inhibiting this process leads to an adaptive hypertrophic vascular response induced by a distinct ß1-mediated FAK phosphorylation pattern.

Influence of Perivascular Adipose Tissue on Microcirculation: A Link Between Hypertension and Obesity.

Alterations in microcirculation play a crucial role in the pathogenesis of cardiovascular and metabolic disorders such as obesity and hypertension. The small resistance arteries of these patients show a typical remodeling, as indicated by an increase of media or total wall thickness to lumen diameter ratio that impairs organ flow reserve. The majority of blood vessels are surrounded by a fat depot which is termed perivascular adipose tissue (PVAT). In recent years, data from several studies have indicated that PVAT is an endocrine organ that can produce a variety of adipokines and cytokines, which may participate in the regulation of vascular tone, and the secretory profile varies with adipocyte phenotype and disease status. The PVAT of lean humans largely secretes the vasodilator adiponectin, which will act in a paracrine fashion to reduce peripheral resistance and improve nutrient uptake into tissues, thereby protecting against the development of hypertension and diabetes. In obesity, PVAT becomes enlarged and inflamed, and the bioavailability of adiponectin is reduced. The inevitable consequence is a rise in peripheral resistance with higher blood pressure. The interrelationship between obesity and hypertension could be explained, at least in part, by a cross-talk between microcirculation and PVAT. In this article, we propose an integrated pathophysiological approach of this relationship, in order to better clarify its role in obesity and hypertension, as the basis for effective and specific prevention and treatment.

Perivascular adipose tissue-derived adiponectin activates BK(Ca) channels to induce anticontractile responses.

This study aims to identify the potential mechanisms by which perivascular adipose tissue (PVAT) reduces tone in small arteries. Small mesenteric arteries from wild-type and large-conductance Ca(2+)-activated K(+) (BKCa) channel knockout mice were mounted on a wire myograph in the presence and absence of PVAT, and contractile responses to norepinephrine were assessed. Electrophysiology studies were performed in isolated vessels to measure changes in membrane potential produced by adiponectin. Contractile responses from wild-type mouse small arteries were significantly reduced in the presence of PVAT. This was not observed in the presence of a BKCa channel inhibitor or with nitric oxide synthase (NOS) inhibition or in BKCa or adiponectin knockout mice. Solution transfer experiments demonstrated the presence of an anticontractile factor released from PVAT. Adiponectin-induced vasorelaxation and hyperpolarization in wild-type arteries were not evident in the absence of or after inhibition of BKCa channels. PVAT from BKCa or adiponectin knockout mice failed to elicit an anticontractile response in wild-type arteries. PVAT releases adiponectin, which is an anticontractile factor. Its effect on vascular tone is mediated by activation of BKCa channels on vascular smooth muscle cells and adipocytes and by endothelial mechanisms.

Retinal arterial hypertrophy: the new LVH?

Prevention of target organ damage represents the El Dorado for clinicians who treat hypertension. Although many of the cardiovascular sequelae of chronic hypertension are due to large artery atherosclerosis, an equal number are due to small artery dysfunction. These microvascular complications include eye disease (retinopathy), kidney failure, diastolic dysfunction of the heart and small vessel brain disease leading to stroke syndromes, dementia and even depression. Examination of the retinal vasculature represents the only way to reliably derive information regarding small arteries responsible for these diverse pathologies. This review aims to summarise the rapidly accruing evidence indicating that easily observable abnormalities of retinal arteries reflect target organ damage elsewhere in the body of hypertensive patients. In tandem, we also present putative mechanisms by which hypertension and diabetes fundamentally change small artery structure and function and how these processes may lead to target organ damage.