Acute Kidney Injury, Microvascular Rarefaction, and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Animal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes. RESULTS: Post-transplant biopsies were performed at a median of 113 days (interquartile range, 101-128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, -3.7%; interquartile range, -6.6% to -0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, -4.5%; interquartile range, -8.0% to -0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, -2.9%; 95% confidence interval, -4.0 to -1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation. CONCLUSIONS: Perioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging.

Vessel loss in the aging brain is commonly reported, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we imaged and quantified vessel length, tortuosity and width in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical grey matter regions, while some regions (visual cortex, amygdala, thalamus) showed no decline with aging. Regions supplied by the anterior cerebral artery were more vulnerable to loss than those supplied by middle or posterior cerebral arteries. Vessel width and tortuosity generally increased with age but neither reliably predicted regional vessel loss. Since capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning, we hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. These findings indicate that age-related vessel loss is region specific and can be explained, at least partially, by regional susceptibilities to capillary plugging.

Training counteracts DEX-induced microvascular rarefaction by improving the balance between apoptotic and angiogenic proteins.

This work investigated the mechanisms induced by exercise training that may contribute to attenuate dexamethasone (DEX)-induced microvascular rarefaction and hypertension. Wistar rats underwent training protocol or were kept sedentary for 8 weeks. Dexamethasone was administered during the following 14-days and hemodynamic parameters were recorded at the end. Capillary density (CD) and capillary-to-fiber ratio (C:F ratio) were obtained in soleus muscle (SOL). Also, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), endothelial nitric oxide synthase (eNOS), B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 (Bax), p-BAX and caspase-3 cleaved protein levels were analyzed. DEX treatment significantly increased blood pressure (+14%), which was associated with reduced C:F ratio (-41.0%) and CD (-43.1%). Reduction of vessel density was associated with decreased VEGF (-15.6%), VEGFR-2 (-14.6%), Bcl-2 (-18.4%), Bcl-2/Bax ratio (-29.0%) and p-Bax/Bax (-25.4%), and also with increased caspase-3 cleaved protein level (25%). Training, on the other hand, prevented microvessels loss by mitigating all proteins changes induced by DEX. In addition, angiogenic and apoptotic proteins were significantly correlated with CD, which, in turn, was associated with blood pressure. Therefore, we may point out that exercise training is a good strategy to attenuate DEX-induced microvascular rarefaction in soleus muscle and this response involves a better balance between apoptotic and angiogenic proteins, which may contribute for the attenuation of hypertension.

Altered ellipsoid zone reflectivity and deep capillary plexus rarefaction correlate with progression in Best disease.

AIMS: To evaluate the effects of neurovascular damage in patients with the typical vitelliform lesion of Best vitelliform macular dystrophy (BVMD) in the attempt to identify different progression patterns. METHODS: Prospective, observational case series. Patients in the vitelliform stage of BVMD and healthy controls underwent complete ophthalmological examination on a yearly basis, including best-corrected visual acuity (BCVA), biomicroscopy, optical coherence tomography (OCT) and OCT angiography (OCT-A). 4.5×4.5 mm OCT-A slabs were imported into ImageJ software and their vessel density (VD) was calculated. Similarly, the ellipsoid zone (EZ) was manually outlined and the reflectivity was measured above the vitelliform lesion and in the 500 µm external to it. Retinal pigment epithelium-Bruch's membrane complex was taken as internal reference. RESULTS: 34 eyes (24 patients) and 34 matched controls were included in the study. Mean follow-up was of 28.4±5.8 months, with 12 eyes showing signs of stage progression at the end follow-up. The EZ overlying the vitelliform lesion and in the peri-lesional area disclosed a significant reduction in reflectivity when compared with the foveal and para-foveal EZ of controls, respectively. VD resulted meaningfully decreased only at the deep capillary plexus. Of notice, more extensive EZ (reflectivity <0.7) and vascular alterations (VD <0.4) at baseline strongly correlated with worse BCVA and were associated with a more rapid progression at follow-up. CONCLUSIONS: Both EZ reflectivity and VD at deep capillary plexus may prove valuable biomarkers to assess BVMD severity and detect progression. In this view, 'rapid progressors' might benefit the most from timely genetic therapies in the future.

Systemic microvascular rarefaction is correlated with dysfunction of late endothelial progenitor cells in mild hypertension: a substudy of EXCAVATION-CHN1.

BACKGROUND: Hypertension often presents with microvascular rarefaction (MVR), which is closely associated with impaired angiogenesis. Early detection of MVR is essential for systemic assessment in patient with hypertension. We aimed to determine the systemic MVR through both optical coherence tomography angiography (OCTA) and intravital capillaroscopy, and to investigate their respective efficacies and related mechanisms associated with late endothelial progenitor cells (LEPCs) dysfunction. METHODS: Seventy-one hypertensive and sixty-nine age-match normotensive subjects were included in this study. All subjects received intravital capillaroscopy for skin capillary density (SCD) and OCTA for retinal capillary density (RCD) and non-perfused areas (R-NPA). Subsequently, correlation of LEPCs activities and microvascular rarefaction were examined. RESULTS: Compared with normotensive subjects, hypertensive patients had significantly lower RCD [(52.9 ± 2.9)% vs. (57.8 ± 1.6)%, P < 0.01] and higher R-NPA [(0.12 ± 0.07) mm2 vs. (0.053 ± 0.020) mm2, P < 0.01]. SCD correlated positively with RCD but negatively with R-NPA [(RCD: OR = 0.40, 95% CI 0.25-0.67, P < 0.01); (R-NPA: OR = 0.39, 95% CI - 0.0029 to 0.0011, P < 0.01)]. The discriminative powers of RCD performed best (AUC 0.79 versus SCD AUC 0.59, P < 0.001) followed by R-NPA (AUC 0.73 versus SCD AUC 0.59, P < 0.001) for systolic blood pressure. Similar pattern is also found for diastolic blood pressure (RCD AUC 0.80 versus SCD AUC 0.54, P < 0.001; R-NPA AUC 0.77 versus SCD AUC 0.54, P < 0.001). Furthermore, LEPCs tube formation was impaired in hypertensive patients (36.8 ± 2.3 vs. 28 ± 3.7, P < 0.01). After multivariate adjustments, positive correlation existed between RCD or R-NPA with LEPCs tube formation (RCD: ß = 0.64, 95% CI 0.34-0.91, P < 0.01; R-NPA: ß = - 24.67, 95% CI - 43.14 to - 4.63, P < 0.05) but not with SCD (ß = 0.082, 95% CI 0.01-0.18, P = 0.085). CONCLUSION: Compared to intravital capillaroscopy, OCTA is a more precise technique for early detection of hypertensive microvascular rarefaction, which is associated with the fall in LEPC-mediated angiogenesis. Both of OCTA and LEPCs function can help identify hypertension-related capillary abnormality. Trail Registration The trial is a substudy of EXCAVATION-CHN1, registered at clinicaltrials.gov as NCT02817204 (June 26, 2016).

Hyperoxia-induced lung structure-function relation, vessel rarefaction, and cardiac hypertrophy in an infant rat model.

BACKGROUND: Hyperoxia-induced bronchopulmonary dysplasia (BPD) models are essential for better understanding and impacting on long-term pulmonary, cardiovascular, and neurological sequelae of this chronic disease. Only few experimental studies have systematically compared structural alterations with lung function measurements. METHODS: In three separate and consecutive series, Sprague-Dawley infant rats were exposed from day of life (DOL) 1 to 19 to either room air (0.21; controls) or to fractions of inspired oxygen (FiO2) of 0.6, 0.8, and 1.0. Our primary outcome parameters were histopathologic analyses of heart, lungs, and respiratory system mechanics, assessed via image analysis tools and the forced oscillation technique, respectively. RESULTS: Exposure to FiO2 of 0.8 and 1.0 resulted in significantly lower body weights and elevated coefficients of lung tissue damping (G) and elastance (H) when compared with controls. Hysteresivity (η) was lower due to a more pronounced increase of H when compared with G. A positive structure-function relation was demonstrated between H and the lung parenchymal content of α-smooth muscle actin (α-SMA) under hyperoxic conditions. Moreover, histology and morphometric analyses revealed alveolar simplification, fewer pulmonary arterioles, increased α-SMA content in pulmonary vessels, and right heart hypertrophy following hyperoxia. Also, in comparison to controls, hyperoxia resulted in significantly lower plasma levels of vascular endothelial growth factor (VEGF). Lastly, rats in hyperoxia showed hyperactive and a more explorative behaviour. CONCLUSIONS: Our in vivo infant rat model mimics clinical key features of BPD. To the best of our knowledge, this is the first BPD rat model demonstrating an association between lung structure and function. Moreover, we provide additional evidence that infant rats subjected to hyperoxia develop rarefaction of pulmonary vessels, augmented vascular α-SMA, and adaptive cardiac hypertrophy. Thus, our model provides a clinically relevant tool to further investigate diseases related to O2 toxicity and to evaluate novel pharmacological treatment strategies.

Early Life Microcirculatory Plasticity and Blood Pressure Changes in Low Birth Weight Infants Born to Normotensive Mothers: A Cohort Study.

BACKGROUND: Capillary rarefaction (CR) is an established hallmark of essential hypertension (EH). The aim of this study was to examine early changes in capillary density (CD) and blood pressure (BP) in low birth weight (LBW) infants who are at risk of developing EH in later life. METHODS: We studied 77 LBW infants and 284 normal birth weight (NBW) infants, all born to mothers with normotension, in a longitudinal multicenter study. Intravital capillaroscopy was used to measure functional basal capillary density (BCD) and maximal capillary density (MCD) at birth, 3, 6, and 12 months. RESULTS: We found that LBW infants, born preterm and at term, had a significantly higher CD at birth, then underwent significant CR in the 1st 3 months culminating in a CD similar to that seen in NBW infants. NBW infants showed a gradual reduction in CD between birth and 12 months. Non-Caucasian ethnicity and preterm birth were significant predictors of a higher CD at birth. Systolic BP in NBW infants increased significantly from birth to 3 months, and we identified a significant negative correlation between systolic BP and MCD. CONCLUSIONS: This study has identified a process of early "accelerated capillary remodeling" in LBW infants, which corrects their higher CD at birth. This remodeling is unlikely to explain the CR seen in adult individuals with, or at risk of developing EH. Further follow-up studies are required to determine the timing and mechanisms involved in CR, which is likely to occur after the 1st year of life but before early adulthood.

Sublingual functional capillary rarefaction in chronic heart failure.

BACKGROUND AND OBJECTIVE: Microcirculatory changes contribute to clinical symptoms and disease progression in chronic heart failure (CHF). A depression of coronary flow reserve is associated with a lower myocardial capillary density in biopsies. We hypothesized that changes in cardiac microcirculation might also be reflected by a systemic reduction in capillaries and visualized by sublingual videomicroscopy. The aim was to study in vivo capillary density and glycocalyx dimensions in patients with CHF vs healthy controls. METHODS: Fifty patients with ischaemic and nonischaemic CHF and standard treatment were compared to 35 healthy age-matched subjects in a prospective cross-sectional study. Sublingual microcirculation was visualized using a sidestream darkfield videomicroscope. Functional and perfused total capillary densities were compared between patients and controls. A reduced glycocalyx thickness was measured by an increased perfused boundary region (PBR). RESULTS: Median functional and total perfused capillary densities were 30% and 45% lower in patients with CHF (both P < .001). Intake of oral vitamin K antagonists was associated with significantly lower capillary densities (P < .05), but not independent of NT-proBNP. Dimensions of the glycocalyx were marginally lower in CHF patients than in healthy controls (<7% difference). However, PBR correlated significantly with inflammation markers (fibrinogen: r = .58; C-reactive protein: r = .42), platelet counts (r = .36) and inversely with measures of liver/renal function such as bilirubin (r = -.38) or estimated glomerular filtration rate (r = -.34) in CHF patients. CONCLUSION: CHF patients have got a markedly lower functional and total perfused capillary density in sublingual microvasculature when compared to controls, indicating a systemic decrease in microcirculation.

Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury.

Damage to endothelial cells contributes to acute kidney injury (AKI) by causing impaired perfusion, while the permanent loss of the capillary network following AKI has been suggested to promote chronic kidney disease. Therefore, strategies to protect renal vasculature may impact both short-term recovery and long-term functional preservation post-AKI. Human adipose stromal cells (hASCs) possess pro-angiogenic and anti-inflammatory properties and therefore have been tested as a therapeutic agent to treat ischaemic conditions. This study evaluated hASC potential to facilitate recovery from AKI with specific attention to capillary preservation and inflammation. Male Sprague Dawley rats were subjected to bilateral ischaemia/reperfusion and allowed to recover for either two or seven days. At the time of reperfusion, hASCs or vehicle was injected into the suprarenal abdominal aorta. hASC-treated rats had significantly greater survival compared to vehicle-treated rats (88.7% versus 69.3%). hASC treatment showed hastened recovery as demonstrated by lower creatinine levels at 48 hrs, while tubular damage was significantly reduced at 48 hrs. hASC treatment resulted in a significant decrease in total T cell and Th17 cell infiltration into injured kidneys at 2 days post-AKI, but an increase in accumulation of regulatory T cells. By day 7, hASC-treated rats showed significantly attenuated capillary rarefaction in the cortex (15% versus 5%) and outer medulla (36% versus 18%) compared to vehicle-treated rats as well as reduced accumulation of interstitial alpha-smooth muscle actin-positive myofibroblasts. These results suggest for the first time that hASCs improve recovery from I/R-induced injury by mechanisms that contribute to decrease in inflammation and preservation of peritubular capillaries.

Is Diabetic Skeletal Fragility Associated with Microvascular Complications in Bone?

PURPOSE OF REVIEW: The objective of this literature review is to determine whether there are indications that microvascular complications occur in diabetic bone. Evidence definitively linking diabetic skeletal fragility with microvascular complications in bone remains elusive. RECENT FINDINGS: Circumstantial evidence, some recent and some lost to time, suggests that atherosclerotic vascular diseases such as peripheral arterial disease cause poor blood perfusion of bone and subsequent hypoxia and contribute to low bone density and high cortical porosity, patterns similar to some recently observed in diabetic subjects. Evidence also exists to suggest that potentially anti-angiogenic conditions, such as impaired vascular endothelial growth factor (VEGF) signaling, predominate in diabetic bone. Microvascular complications may contribute, in part, to diabetic skeletal fragility but data supporting this interpretation are primarily circumstantial at this time. This review highlights gaps in our knowledge and hopefully spurs further discussions and research on this topic.

The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats.

Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to-fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats (n = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats (n = 10) as controls. The STZ-treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (H2O) treatment groups: nondiabetic-SED-H2O, STZ-SED-H2O, STZ-EX-H2O, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-H2O animals (both P < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 ± 0.12 and 2.04 ± 0.03 vs 1.71 ± 0.09, P < 0.05) and the soleus (2.36 ± 0.07 and 2.68 ± 0.14 vs 2.13 ± 0.12, P < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 ± 0.07, P < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels (r2 = -0.7015, P < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose (P < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone (P < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D.NEW & NOTEWORTHY It is currently well established that poorly controlled diabetes reduces both skeletal muscle mass and muscle capillarization. These muscle-specific features of diabetes may, in turn, compromise insulin sensitivity and glucose control. Using a model of streptozotocin-induced diabetes, we show the vascular complications linked with disease and how chronic exposure to exercise and prazosin (an α1-adrenergic antagonist) can reduce these complications and improve glycemic control.

The right ventricle and pulmonary hypertension.

In patients with pulmonary hypertension (PH), the primary cause of death is right ventricular (RV) failure. Improvement in RV function is therefore one of the most important treatment goals. In order to be able to reverse RV dysfunction and also prevent RV failure, a detailed understanding of the pathobiology of RV failure and the underlying mechanisms concerning the transition from a pressure-overloaded adapted right ventricle to a dilated and failing right ventricle is required. Here, we propose that insufficient RV contractility, myocardial fibrosis, capillary rarefaction, and a disturbed metabolism are important features of a failing right ventricle. Furthermore, an overview is provided about the potential direct RV effects of PH-targeted therapies and the effects of RV-directed medical treatments.