Off the Beaten Path in Oncology: Active Brown Adipose Tissue by Virtue of Molecular Imaging.

Brown Adipose Tissue (BAT) is considered beneficial in diabetes and obesity, but it can also have negative effects such as its implication in tumours' pathogenesis and the development of Cancer-induced Cachexia. Since 18F-FDG PET/CT is a common molecular imaging modality used in cancer assessment, we aim to study the 18F-FDG BAT biodistribution in oncological patients and look for possible correlations between BAT activity and different malignancies as well as the patient's weight status. After analysing the total number of oncological 18F-FDG PET/CT scans between 2017 and 2021, we selected patients with active BAT. Based on their BMI, the selected patients were divided into nonobese (NO) vs. overweight and obese (OOB). OOB SUVmaxlean body mass(LBM) had the highest mean values in supraclavicular, latero-cervical, and paravertebral vs. mediastinal and latero-thoracic localisations in NO. BMI was positively correlated with latero-cervical and supraclavicular SUVmax(LBM) but negatively correlated with latero-thoracic and abdominal SUVmax(LBM). Considering the age of the patients, SUVmax(LBM) decreases in the latero-cervical, paravertebral, and abdominal regions. In addition, the males presented lower SUVmax(LBM) values. SUVmax(LBM) was not affected by the treatment strategy or the oncological diagnosis. To conclude, it is mandatory to take into consideration the BAT particularities and effects on weight status in order to optimise the clinical management of oncological patients.

Role of the heart in blood pressure lowering during chronic baroreflex activation: insight from an in silico analysis.

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

The baroreflex as a long-term controller of arterial pressure.

Because of resetting, a role for baroreflexes in long-term control of arterial pressure has been commonly dismissed in the past. However, in recent years, this perspective has changed. Novel approaches for determining chronic neurohormonal and cardiovascular responses to natural variations in baroreceptor activity and to electrical stimulation of the carotid baroreflex indicate incomplete resetting and sustained responses that lead to long-term alterations in sympathetic activity and arterial pressure.

Renal denervation for the treatment of resistant hypertension: review and clinical perspective.

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans.

Baroreflex activation: from mechanisms to therapy for cardiovascular disease.

Recent technical advances have led to the development of a medical device that can reliably activate the carotid baroreflex with an acceptable degree of safety. Because activation of the sympathetic nervous system plays an important role in the pathogenesis of hypertension and heart failure, the unique ability of this device to chronically suppress central sympathetic outflow in a controlled manner suggests potential value in the treatment of these conditions. This notion is supported by both clinical and experimental animal studies, and the major aim of this article is to elucidate the physiological mechanisms that account for the favorable effects of baroreflex activation therapy in patients with resistant hypertension and heart failure. Illumination of the neurohormonal, renal, and cardiac actions of baroreflex activation is likely to provide the means for better identification of those patients that are most likely to respond favorably to this device-based therapy.

Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension.

The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation-current therapies in patients with resistant hypertension, who are commonly obese-restore cardiovascular dynamic control. Increases in body weight to ∼150% of control led to a gradual increase in mean arterial pressure to 17 ± 3 mmHg above control (100 ± 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1-4 days on high-fat intake, reaching 130 ± 4 beats per minute (bpm) (control = 86 ± 3 bpm) and ∼45% and <20%, respectively, of control levels. Subsequently, both baroreflex activation and renal denervation abolished the hypertension. However, only baroreflex activation effectively attenuated the tachycardia and restored cardiac baroreflex sensitivity and heart rate variability. These findings suggest that baroreflex activation therapy may reduce the risk factors for cardiac arrhythmias as well as lower arterial pressure.

The sympathetic nervous system in obesity hypertension.

Abundant evidence supports a role of the sympathetic nervous system in the pathogenesis of obesity-related hypertension. However, the nature and temporal progression of mechanisms underlying this sympathetically mediated hypertension are incompletely understood. Recent technological advances allowing direct recordings of renal sympathetic nerve activity (RSNA) in conscious animals, together with direct suppression of RSNA by renal denervation and reflex-mediated global sympathetic inhibition in experimental animals and human subjects have been especially valuable in elucidating these mechanisms. These studies strongly support the concept that increased RSNA is the critical mechanism by which increased central sympathetic outflow initiates and maintains reductions in renal excretory function, causing obesity hypertension. Potential determinants of renal sympathoexcitation and the differential mechanisms mediating the effects of renal-specific versus reflex-mediated, global sympathetic inhibition on renal hemodynamics and cardiac autonomic function are discussed. These differential mechanisms may impact the efficacy of current device-based approaches for hypertension therapy.

A novel device and system concept for therapeutic plasma exchange in rats.

INTRODUCTION: Therapeutic plasma exchange (TPE) has been developed more than 100 years ago in an animal model and adapted to humans 30 years later. Since then, the TPE research on animal models is lacking, mainly due to difficulties raised by the scaling of the plasmapheresis unit so that the animal's cardiovascular parameters are not considerably affected. METHODS: The system concept of a novel TPE device with continuous hemodynamic monitoring in small rodent models has been used. RESULTS: A continuum TPE unit for rats has been developed, able to produce up to 95% plasma exchange rate without any TPE-related hemodynamic impairment, monitored up to 35 days after the procedure. CONCLUSION: The TPE unit for rats was able to produce 95% plasma exchange rate in non-anesthetized animals, enabling a full translation of the human TPE into an animal model. The newly developed plasmapheresis unit enable a wide range of more accurate preclinical evaluation, with cardiac parameters monitoring, using small rodents in awaken state.

Experimental Models for Controlled Burn Injuries in Rats: A Systematic Analysis of Original Methods and Burn Devices.

Despite a wide variety of models found in literature, choosing the right one can be difficult as many of them are lacking precise methodology. This study aims to analyze and compare original burn models in terms of burn device and technique, parameters, and wound depth assessment. A systematic search was performed according to PRISMA guidelines on studies describing original experimental burn models in rats. The adapted PICO formula and ARRIVE checklist were followed for inclusion and assessment of quality of studies. Characteristics of animals, burn technique, burn parameters, and method of histological confirmation of burn depth were recorded. Twenty-seven studies were included in the final analysis. Most studies used direct contact with skin for burn infliction (n = 20). The rat's dorsum was the most common site (n = 18). Ten studies used manually controlled burn devices, while 10 designed automatic burn devices with control over temperature (n = 10), exposure time (n = 5), and pressure (n = 5). Most studies (n = 7) used a single biopsy taken from the center of the wound to confirm burn depth immediately after burn infliction. From the wide variety of burn models in current literature, our study provides an overview of the most relevant experimental burn models in rats aiding researchers to understand what needs to be addressed when designing their burn protocol. Models cannot be compared as burn parameters variate significantly. Assessment of burn depth should be done in a standardized, sequential fashion in future burn studies to increase reproducibility.

Pepsin and the Lung-Exploring the Relationship between Micro-Aspiration and Respiratory Manifestations of Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is one of the most commonly encountered disorders in clinical practice nowadays, with an increasing burden on healthcare systems worldwide. GERD-related respiratory symptoms such as unexplained chronic cough, bronchial asthma or chronic obstructive pulmonary disease (COPD) with frequent exacerbations often pose diagnostic and therapeutic challenges and may require a multidisciplinary approach. Moreover, a potential role of GERD as a risk factor has been proposed for chronic rejection in patients who underwent lung transplantation. Pepsin has gained considerable attention from the scientific community in the last few years as a possible surrogate biomarker for GERD. The aim of this narrative review was to provide an overview of the potential utility of pepsin detection as a marker of micro-aspiration in various biological fluids retrieved from patients with suspected GERD-induced respiratory manifestations and in lung transplant patients with allograft dysfunction. Data on the subject remains highly contradictory, and while certain studies support its applicability in investigating atypical GERD manifestations, at the moment, it would be realistic to accept a modest utility at best. A major lack of consensus persists regarding topics such as the optimal timeframe for fluid collection and cut-off values. Further research is warranted in order to address these issues.

Targeted Cancer Therapy via pH-Functionalized Nanoparticles: A Scoping Review of Methods and Outcomes.

(1) Background: In recent years, several studies have described various and heterogenous methods to sensitize nanoparticles (NPs) to pH changes; therefore, in this current scoping review, we aimed to map current protocols for pH functionalization of NPs and analyze the outcomes of drug-loaded pH-functionalized NPs (pH-NPs) when delivered in vivo in tumoral tissue. (2) Methods: A systematic search of the PubMed database was performed for all published studies relating to in vivo models of anti-tumor drug delivery via pH-responsive NPs. Data on the type of NPs, the pH sensitization method, the in vivo model, the tumor cell line, the type and name of drug for targeted therapy, the type of in vivo imaging, and the method of delivery and outcomes were extracted in a separate database. (3) Results: One hundred and twenty eligible manuscripts were included. Interestingly, 45.8% of studies (n = 55) used polymers to construct nanoparticles, while others used other types, i.e., mesoporous silica (n = 15), metal (n = 8), lipids (n = 12), etc. The mean acidic pH value used in the current literature is 5.7. When exposed to in vitro acidic environment, without exception, pH-NPs released drugs inversely proportional to the pH value. pH-NPs showed an increase in tumor regression compared to controls, suggesting better targeted drug release. (4) Conclusions: pH-NPs were shown to improve drug delivery and enhance antitumoral effects in various experimental malignant cell lines.

Brown Adipose Tissue Biodistribution and Correlations Particularities in Parathyroid Pathology Personalized Diagnosis.

Brown adipose tissue (BAT) participates in the regulation of whole-body metabolism by producing a variety of adipokines. This study investigates into the BAT pattern and the clinical aspects of overweight and obese (OOB) vs. non-obese (NO) hyperparathyroidism (HPT) patients with the aim of assessing the impact of BAT and obesity on HPT. Parathyroid scans performed on 441 HPT patients between 2015 and 2020 were retrospectively analyzed in order to select the images with active BAT. Based on their BMI, the patients with active BAT were divided into OOB vs. NO. The results showed that BAT was present in cervical and supraclavicular regions, with a single localization especially among NO vs. multiple sites among OOB. The (total counts/pixels)BAT/(total counts/pixels)non-BAT ratio in the right cervical localization showed a significant difference between the groups with higher values in OOB. BMI, PTH, FT4, vitamin D, magnesium, creatinine, and urea had significant correlations with BAT ratios. The predictive values showed that right cervical ratios higher than 1.52 and right supraclavicular ratios lower than 1.15 indicated an increased probability of being OOB. The significant correlations between BAT activation in OOB vs. NO and HPT clinical parameters could be useful for developing potential treatments based on this tissue.

Modern Approaches for the Treatment of Heart Failure: Recent Advances and Future Perspectives.

Heart failure (HF) is a progressively deteriorating medical condition that significantly reduces both the patients' life expectancy and quality of life. Even though real progress was made in the past decades in the discovery of novel pharmacological treatments for HF, the prevention of premature deaths has only been marginally alleviated. Despite the availability of a plethora of pharmaceutical approaches, proper management of HF is still challenging. Thus, a myriad of experimental and clinical studies focusing on the discovery of new and provocative underlying mechanisms of HF physiopathology pave the way for the development of novel HF therapeutic approaches. Furthermore, recent technological advances made possible the development of various interventional techniques and device-based approaches for the treatment of HF. Since many of these modern approaches interfere with various well-known pathological mechanisms in HF, they have a real ability to complement and or increase the efficiency of existing medications and thus improve the prognosis and survival rate of HF patients. Their promising and encouraging results reported to date compel the extension of heart failure treatment beyond the classical view. The aim of this review was to summarize modern approaches, new perspectives, and future directions for the treatment of HF.

Systems biology and integrative physiological modelling.

Over the last 10 years, 'Systems Biology' has focused on the integration of biology and medicine with information technology and computation. The current challenge is to use the discoveries of the last 20 years, such as genomics and proteomics, to develop targeted therapeutical strategies. These strategies are the result of understanding the aetiologies of complex diseases. Scientists predict the data will make personalized medicine rapidly available. However, the data need to be considered as a highly complex system comprising multiple inputs and feedback mechanisms. Translational medicine requires the functional and conceptual linkage of genetics to proteins, proteins to cells, cells to organs, organs to systems and systems to the organism. To help understand the complex integration of these systems, a mathematical model of the entire human body, which accurately links the functioning of all organs and systems together, could provide a framework for the development and testing of new hypotheses that will be important in clinical outcomes. There are several efforts to develop a 'Human Physiome', with the strengths and weaknesses of each being presented here. The development of a 'Human Model', with verification, documentation and validation of the underlying and integrative responses, is essential to provide a usable environment. Future development of a 'Human Model' requires integrative physiologists working in collaboration with other scientists, who have expertise in all areas of human biology, to develop the most accurate and usable human model.

Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus.

Inflammation and immune system dysfunction contributes to the development of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that carries a high risk for both renal and cardiovascular disease. While hemodynamic changes that may contribute to increased cardiovascular risk have been reported in humans and animal models of SLE, renal hemodynamics have not been widely studied. The renin-angiotensin system (RAS) plays a central role in renal hemodynamic control, and although RAS blockade is a common therapeutic strategy, the role of RAS in hemodynamic function during SLE is not clear. This study tested whether mean arterial pressure (MAP) and renal hemodynamic responses to acute infusions of ANG II in anesthetized animals were enhanced in an established female mouse model of SLE (NZBWF1). Baseline MAP was not different between anesthetized SLE and control (NZWLacJ) mice, while renal blood flow (RBF) was significantly lower in mice with SLE. SLE mice exhibited an enhanced pressor response and greater reduction in RBF after ANG II infusion. An acute infusion of the ANG II receptor blocker losartan increased RBF in control mice but not in mice with SLE. Renin and ANG II type 1 receptor expression was significantly lower, and ANG II type 2 receptor expression was increased in the renal cortex from SLE mice compared with controls. These data suggest that there are fewer ANG II receptors in the kidneys from mice with SLE but that the existing receptors exhibit an enhanced sensitivity to ANG II.

Smartphone ownership and use of mental health applications by psychiatric inpatients.

Little is known about the use of mental health smartphone applications during the greatest period of vulnerability - immediately following discharge from a psychiatric inpatient unit. Currently, no data are available regarding smartphone ownership or technology literacy of individuals who receive inpatient psychiatric treatment. The goal of this study was to determine psychiatric inpatients' smartphone ownership, current uses of, and interest in utilizing apps to aid in mental health treatment after discharge. A single time point self-report survey was given to patients prior to discharge from a psychiatric inpatient unit at a major academic hospital in a metropolitan area of the United States. Of the 101 survey respondents, 82.8% indicated that they own a smartphone, and over 70% indicated that they use smartphone apps, can access the internet from their phones, and use social media. While only 25.3% reported that they currently use a mental health app, a majority of respondents (53.2%) expressed interest in using such apps in the future, and almost 60% would use those apps to track their mental health. Our data suggest that there is significant untapped potential for utilizing smartphone applications for psychiatric monitoring and treatment following discharge from an inpatient psychiatric unit.

Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex.

Following sinoaortic denervation, which eliminates arterial baroreceptor input into the brain, there are slowly developing adaptations that abolish initial sympathetic activation and hypertension. In comparison, electrical stimulation of the carotid sinus for 1 wk produces sustained reductions in sympathetic activity and arterial pressure. However, whether compensations occur subsequently to diminish these responses is unclear. Therefore, we determined whether there are important central and/or peripheral adaptations that diminish the sympathoinhibitory and blood pressure-lowering effects of more sustained carotid sinus stimulation. To this end, we measured whole body plasma norepinephrine spillover and alpha(1)-adrenergic vascular reactivity in six dogs over a 3-wk period of baroreflex activation. During the first week of baroreflex activation, there was an approximately 45% decrease in plasma norepinephrine spillover, along with reductions in mean arterial pressure and heart rate of approximately 20 mmHg and 15 beats/min, respectively; additionally, plasma renin activity did not increase. Most importantly, these responses during week 1 were largely sustained throughout the 3 wk of baroreflex activation. Acute pressor responses to alpha-adrenergic stimulation during ganglionic blockade were similar throughout the study, indicating no compensatory increases in adrenergic vascular reactivity. These findings indicate that the sympathoinhibition and lowering of blood pressure and heart rate induced by chronic activation of the carotid baroreflex are not diminished by adaptations in the brain and peripheral circulation. Furthermore, by providing evidence that baroreflexes have long-term effects on sympathetic activity and arterial pressure, they present a perspective that is opposite from studies of sinoaortic denervation.

Progressive renal vascular proliferation and injury in obese Zucker rats.

OBJECTIVE: Obesity, an independent risk factor for chronic kidney disease, may induce renal injury by promoting inflammation. Inflammatory cytokines can induce neovascularization in different organs, including the kidneys. However, whether obesity triggers renal neovascularization and, if so, its effect on renal function has never been investigated. METHODS: Blood pressure, proteinuria, and glomerular filtration rate (GFR) were measured in vivo. Renal microvascular (MV) architecture was studied by 3D micro-CT in lean and obese Zucker rats (LZR and OZR, n = 7/group) at 12, 22, and 32 weeks of age. Renal inflammation was assessed by quantifying interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and ED-1 expression, as renal fibrosis in trichrome-stained cross-sections. RESULTS: Mild inflammation and lower GFR was only observed in younger OZR, without renal fibrosis or changes in MV density. Interestingly, renal MV density increased in OZR at 32 weeks of age, accompanied by pronounced increase in renal IL-6 and TNF-alpha, ED-1+ cells, proteinuria, decreased GFR, and fibrosis. CONCLUSIONS: This study shows increased renal cortical vascularization in experimental obesity, suggesting neovascularization as an evolving process as obesity progresses. Increased renal vascularization, possibly triggered by inflammation, may reflect an initially compensatory mechanism in obesity. However, increased inflammation and inflammatory-induced neovascularization may further promote renal injury as obesity advances.

Refractory blood pressure in female SHR to increased oxidative stress is not mediated by NO or by upregulation of renal antioxidant enzymes.

There is a sex difference in the blood pressure (BP) responses to prooxidants and antioxidants in the spontaneously hypertensive rat (SHR). In contrast to males, BP in female SHR does not decrease in response to antioxidants, such as tempol or apocynin, or increase in response to the prooxidant, molsidomine. Molsidomine decreases BP and increases expression of antioxidants in male Wistar-Kyoto rats (WKY), but not male SHR. The present study tested the hypothesis that the mechanism responsible for the lack of a pressor response to molsidomine in females is due to higher endogenous nitric oxide (NO) or to compensatory upregulation of renal antioxidant enzymes. Female SHR were treated with molsidomine in the presence or absence of nitro-L-arginine methyl ester (L-NAME) for 2 wk. Molsidomine increased nitrate/nitrite (NO(x)) and F2-isoprostane (F2-IsoP) excretion, whereas L-NAME reduced NO(x) but increased F-Isop. Molsidomine and L-NAME together further reduced NO(x) and increased F2-IsoP. Molsidomine alone had no effect on BP; L-NAME alone increased BP. The combination of molsidomine and L-NAME did not increase BP above L-NAME alone levels. Whole body and renal oxidative stress increased, while renal cortical Cu,Zn-SOD expression was downregulated and catalase was upregulated by molsidomine; glutathione peroxidase expression was unaffected. These data support our previous studies suggesting that BP in female SHR is independent of either increases or decreases in oxidative stress. The mechanisms responsible for the sex difference in BP response to increase or decrease of oxidative stress are not due to increased NO in females or to compensatory upregulation of antioxidant enzymes in response to increases in oxidants.

Role of renal microcirculation in experimental renovascular disease.

BACKGROUND: Renal artery stenosis (RAS) causes renal injury partly via microvascular (MV) endothelial dysfunction and damage. Vascular endothelial growth factor (VEGF) is crucial for preservation of microvasculature and promotes vascular proliferation and endothelial repair. We have previously shown that MV rarefaction is associated with decreased VEGF in the kidney exposed to chronic RAS, accompanied by deteriorated renal function and fibrosis. We hypothesized that preserving the renal microcirculation in the stenotic kidney will halt the progression of renal damage. METHODS: Unilateral RAS was induced in 16 pigs. In eight, VEGF (0.05 micrograms/kg) was infused intra-renally at the onset of RAS. After 6 weeks, single-kidney haemodynamics and function were assessed using in vivo multi-detector computed tomography (CT). Renal microvessels, angiogenic pathways and morphology were investigated ex vivo using micro-CT, real-time PCR and histology. RESULTS: Blood pressure and degree of RAS was similar in RAS and RAS + VEGF pigs. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in RAS compared to Normal (221.1 +/- 46.5 and 29.9 +/- 3.8 vs. 522.5 +/- 60.9 and 49.3 +/- 3.4 mL/min, respectively, P < 0.05), accompanied by decreased cortical MV density and increased renal fibrosis. Pre-emptive administration of VEGF preserved MV architecture, attenuated fibrosis and normalized RBF and GFR (510.8 +/- 50.9 and 39.9.1 +/- 4.1 mL/min, P = not significant vs. Normal). CONCLUSIONS: This study underscores the importance of the renal microcirculation in renovascular disease. Intra-renal administration of VEGF preserved renal MV architecture and function of the stenotic kidney, which in turn preserved renal haemodynamics and function and decreased renal fibrosis. These observations suggest that preventing renal MV loss may be a potential target for therapeutic approaches for patients with chronic renovascular disease.