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The microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature in ex vivo systems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculature de novo ( e.g ., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments., Competing Interests: Conflict of Interest. LH and AF are the founders of OncoFluidics, a startup that seeks to commercialize microfluidic drug tests using intact tissues. All the authors declare no conflict of interest.

Purpose: To assess the alteration in the macular microvascular in type 2 diabetic patients with peripheral neuropathy (DPN) and without peripheral neuropathy (NDPN) by optical coherence tomography angiography (OCTA) and explore the correlation between retinal microvascular abnormalities and DPN disease.Methods: Twenty-seven healthy controls (42 eyes), 36 NDPN patients (62 eyes), and 27 DPN patients (40 eyes) were included. OCTA was used to image the macula in the superficial vascular complex (SVC) and deep vascular complex (DVC). In addition, a state-of-the-art deep learning method was employed to quantify the microvasculature of the two capillary plexuses in all participants using vascular length density (VLD).Results: Compared with the healthy control group, the average VLD values of patients with DPN in SVC (p = 0.010) and DVC (p = 0.011) were significantly lower. Compared with NDPN, DPN patients showed significantly reduced VLD values in the SVC (p = 0.006) and DVC (p = 0.001). Also, DPN patients showed lower VLD values (p < 0.05) in the nasal, superior, temporal and inferior sectors of the inner ring of the SVC when compared with controls; VLD values in NDPN patients were lower in the nasal section of the inner ring of SVC (p < 0.05) compared with healthy controls. VLD values in the DVC (AUC = 0.736, p < 0.001) of the DPN group showed a higher ability to discriminate microvascular damage when compared with NDPN.Conclusion: OCTA based on deep learning could be potentially used in clinical practice as a new indicator in the early diagnosis of DM with and without DPN.

Odontocetes are breath-hold divers with a suite of physiological, anatomical, and behavioral adaptations that are highly derived and vastly different from those of their terrestrial counterparts. Because of these adaptations for diving, odontocetes were originally thought to be exempt from the harms of nitrogen gas embolism while diving. However, recent studies have shown that these mammals may alter their dive behavior in response to anthropogenic sound, leading to the potential for nitrogen supersaturation and bubble formation which may cause decompression sickness in the central nervous system (CNS). We examined the degree of interface between blood, gases, and neural tissues in the spinal cord by quantifying its microvascular characteristics in five species of odontocetes (Tursiops truncatus, Delphinus delphis, Grampus griseus, Kogia breviceps, and Mesoplodon europaeus) and a model terrestrial species (the pig-Sus scrofa domesticus) for comparison. This approach allowed us to compare microvascular characteristics (microvascular density, branching, and diameter) at several positions (cervical, thoracic, and lumbar) along the spinal cord from odontocetes that are known to be either deep or shallow divers. We found no significant differences (p < 0.05 for all comparisons) in microvessel density (9.30–11.18%), microvessel branching (1.60–2.12 branches/vessel), or microvessel diameter (11.83–16.079 µm) between odontocetes and the pig, or between deep and shallow diving odontocete species. This similarity of spinal cord microvasculature anatomy in several species of odontocetes as compared to the terrestrial mammal is in contrast to the wide array of remarkable physio-anatomical adaptations marine mammals have evolved within their circulatory system to cope with the physiological demands of diving. These results, and other studies on CNS lipids, indicate that the spinal cords of odontocetes do not have specialized features that might serve to protect them from Type II DCS.

Microvascular diseases are among the most clinically important diseases, and vascular abnormalities are central in the development of such diseases. Pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, exerts antiangiogenic effects without affecting the structure and function of normal blood vessels. PEDF also has neurotrophic effects, which may be a potential direction for the future treatment of angiogenic diseases with lower side effects. Here, we review (i) the expression levels of PEDF in several important organs and clinically common microvascular diseases and (ii) the effects of its absence and presence on the vasculature and nerves, focusing on both angiogenic and neuroprotective aspects. These effects are both positive and negative, and have the potential to be exploited. Additionally, we summarize and compare various PEDF agents and their possible advantages and disadvantages as therapeutic agents, which, despite most still being in the experimental stage, may provide some new opportunities for future clinical treatments and interventions in PEDF-targeted microvascular diseases. [Display omitted] • 1.The clinical dangers of microvascular disease have become increasingly important. • Pigment epithelium-derived factor has a strong connection to microvasculature. • Targeted therapy is of great significance for microvascular diseases. [ABSTRACT FROM AUTHOR]

Women with a history of gestational diabetes mellitus (GDM) are twice as likely to develop cardiovascular disease (CVD) and ~7 times as likely to develop type 2 diabetes as their age-matched counterparts. However, the mechanism(s) mediating these associations remain unclear. We hypothesized that endothelium- and (nitric oxide) NO-dependent dilation would be attenuated through oxidant stress mechanisms in the microvasculature of women with a history of GDM compared with control women with a history of uncomplicated pregnancy (HC). Ten HC (35 ± 4 yr) and 10 GDM (34 ± 4 yr) underwent a standard local heating protocol (42°C; 0.1°C·s¹). Two intradermal microdialysis fibers were placed in the ventral forearm for local delivery of lactated Ringer's (control) or 5 mM L-ascorbate. After full expression of the local heating response, 15 mM NG-nitro-L-arginine methyl ester (NO synthase inhibition) was perfused. Red cell flux was measured continuously by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC = flux/MAP) was standardized to maximum (% CVCmax; 28 mM SNP + 43°C). Urine albumin:creatinine ratio (ACR) was measured. GDM had attenuated endothelium-dependent (GDM: 67 ± 7 vs. HC: 90 ± 4% CVCmax; P < 0.001) and NO-dependent (GDM: 54 ± 7 vs. HC: 71 ± 3% CVCmax; P = 0.001) dilation at the control site and tended to have higher urine ACR (P = 0.06). Both endothelium-dependent (R² = 0.53, P = 0.02) and NO-dependent (R² = 0.56, P = 0.01) dilation were related to urine ACR in GDM. L-ascorbate perfusion improved endothelium-dependent (82 ± 5% CVCmax; P = 0.03 vs. control) and NO-dependent (68 ± 5% CVCmax; P = 0.02 vs. control) dilation in GDM but had no effect in HC (P > 0.05). Otherwise healthy women with a history of GDM have attenuated microvascular endothelial function and this dysfunction is mediated, in part, by oxidative stress. [ABSTRACT FROM AUTHOR]

The contribution of radiotherapy, per se, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches. [ABSTRACT FROM AUTHOR]

The rapidly growing field of tissue engineering hopes to soon address the shortage of transplantable tissues, allowing for precise control and fabrication that could be made for each specific patient. The protocols currently in place to print large-scale tissues have yet to address the main challenge of nutritional deficiencies in the central areas of the engineered tissue, causing necrosis deep within and rendering it ineffective. Bioprinted microvasculature has been proposed to encourage angiogenesis and facilitate the mobility of oxygen and nutrients throughout the engineered tissue. An implant made via an inkjet printing process containing human microvascular endothelial cells was placed in both B17-SCID and NSG-SGM3 animal models to determine the rate of angiogenesis and degree of cell survival. The implantable tissues were made using a combination of alginate and gelatin type B; all implants were printed via previously published procedures using a modified HP inkjet printer. Histopathological results show a dramatic increase in the average microvasculature formation for mice that received the printed constructs within the implant area when compared to the manual and control implants, indicating inkjet bioprinting technology can be effectively used for vascularization of engineered tissues. [ABSTRACT FROM AUTHOR]

BackgroundCerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development.MethodsThe effect of PDE3A pathway inhibition was studied in the inflammation-induced and cerebral amyloid angiopathy (CAA)-associated mouse models of CMH. The PDE3A pathway was modulated using two approaches: genetic deletion of PDE3A and pharmacological inhibition of PDE3A by cilostazol. The effects of PDE3A pathway modulation on H&E- and Prussian blue (PB)-positive CMH development, BBB function (IgG, claudin-5, and fibrinogen), and neuroinflammation (ICAM-1, Iba-1, and GFAP) were investigated.ResultsRobust development of CMH in the inflammation-induced and CAA-associated spontaneous mouse models was observed. Inflammation-induced CMH were associated with markers of BBB dysfunction and inflammation, and CAA-associated spontaneous CMH were associated primarily with markers of neuroinflammation. Genetic deletion of the PDE3A gene did not alter BBB function, microglial activation, or CMH development, but significantly reduced endothelial and astrocyte activation in the inflammation-induced CMH mouse model. In the CAA-associated CMH mouse model, PDE3A modulation via pharmacological inhibition by cilostazol did not alter BBB function, neuroinflammation, or CMH development.ConclusionsModulation of the PDE3A pathway, either by genetic deletion or pharmacological inhibition, does not alter CMH development in an inflammation-induced or in a CAA-associated mouse model of CMH. The role of microglial activation and BBB injury in CMH development warrants further investigation.

The retinal vasculature is affected in a number of clinically important retinopathies, including diabetic retinopathy. There has been a considerable amount of research into the pathogenesis of retinal microvascular diseases, but the potential contribution of the most abundant cell population in the retina, photoreceptor cells, has been largely overlooked. This review summarizes ongoing research suggesting that photoreceptor cells play a critical role in the development of retinal vascular disease in diabetic retinopathy and other retinopathies.

Summary: In this study, we report static and perfused models of human myocardial-microvascular interaction. In static culture, we observe distinct regulation of electrophysiology of human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in co-culture with human cardiac microvascular endothelial cells (hCMVECs) and human left ventricular fibroblasts (hLVFBs), including modification of beating rate, action potential, calcium handling, and pro-arrhythmic substrate. Within a heart-on-a-chip model, we subject this three-dimensional (3D) co-culture to microfluidic perfusion and vasculogenic growth factors to induce spontaneous assembly of perfusable myocardial microvasculature. Live imaging of red blood cells within myocardial microvasculature reveals pulsatile flow generated by beating hiPSC-CMs. This study therefore demonstrates a functionally vascularized in vitro model of human myocardium with widespread potential applications in basic and translational research. Motivation: In vivo, capillaries communicate with beating myocardium to regulate heart homeostasis, with disruption of communication between microvascular endothelial cells (MVECs) and cardiomyocytes (CMs) causing transition from healthy to disease phenotype. However, much remains unknown about the molecular mechanisms related to CM-EC communication. This had led to a lack of treatment options for diseases in which the myocardial microvascular is compromised, such as cardiac microvascular dysfunction (CMD). Our understanding has been limited by a lack of in vitro models that recapitulate microvascular architectures and the contractile and hemodynamic biomechanics of the beating heart.

Tissue-engineered skin constructs have been under development since the 1980s as a replacement for human skin tissues and animal models for therapeutics and cosmetic testing. These have evolved from simple single-cell assays to increasingly complex models with integrated dermal equivalents and multiple cell types including a dermis, epidermis, and vasculature. The development of micro-engineered platforms and biomaterials has enabled scientists to better recreate and capture the tissue microenvironment in vitro, including the vascularization of tissue models and their integration into microfluidic chips. However, to date, microvascularized human skin equivalents in a microfluidic context have not been reported. Here, we present the design of a novel skin-on-a-chip model integrating human-derived primary and immortalized cells in a full-thickness skin equivalent. The model is housed in a microfluidic device, in which a microvasculature was previously established. We characterize the impact of our chip design on the quality of the microvascular networks formed and evidence that this enables the formation of more homogenous networks. We developed a methodology to harvest tissues from embedded chips, after 14 days of culture, and characterize the impact of culture conditions and vascularization (including with pericyte co-cultures) on the stratification of the epidermis in the resulting skin equivalents. Our results indicate that vascularization enhances stratification and differentiation (thickness, architecture, and expression of terminal differentiation markers such as involucrin and transglutaminase 1), allowing the formation of more mature skin equivalents in microfluidic chips. The skin-on-a-chip tissue equivalents developed, because of their realistic microvasculature, may find applications for testing efficacy and safety of therapeutics delivered systemically, in a human context.

The contribution of radiotherapy, per se, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches.

Background The sympathetic cotransmitter, neuropeptide Y (NPY), is released into the coronary sinus during ST‐segment–elevation myocardial infarction and can constrict the coronary microvasculature. We sought to establish whether peripheral venous (PV) NPY levels, which are easy to obtain and measure, are associated with microvascular obstruction, myocardial recovery, and prognosis. Methods and Results NPY levels were measured immediately after primary percutaneous coronary intervention and compared with angiographic and cardiovascular magnetic resonance indexes of microvascular function. Patients were prospectively followed up for 6.4 (interquartile range, 4.1–8.0) years. PV (n=163) and coronary sinus (n=68) NPY levels were significantly correlated (r=0.92; P21.4 pg/mL by binary recursive partitioning) were associated with increased incidence of heart failure and mortality (hazard ratio, 3.49 [95% CI, 1.65–7.4]; P

Abstract Aims Analysis of microvascular parameters in the retinal circulation—known to reflect those in the systemic circulation—allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid‐range ejection fraction. Methods and results Forty subjects with CHF underwent measurement of retinal capillary flow (RCF), wall‐to‐lumen ratio (WLR), vessel and lumen diameter, wall thickness, and wall cross‐sectional area (WCSA) of retinal arterioles of the right eye by scanning laser Doppler flowmetry (SLDF). Applying a matched pair approach, we compared this group with reference values of age‐matched controls from a random sample in the population of Pilsen, Czech Republic. There was no significant difference in RCF and WLR between the groups (RCF: P = 0.513; WLR: P = 0.106). In contrast, wall thickness and WCSA, indicators of hypertrophic remodelling, were higher in CHF subjects (WT: 15.0 ± 4.2 vs. 12.7 ± 4.2 μm, P = 0.021; WCSA: 4437.6 ± 1314.5 vs. 3615.9 ± 1567.8 μm2, P = 0.014). Similarly, vessel (109.4 ± 11.1 vs. 100.5 ± 14.4 μm, P = 0.002) and lumen diameter (79.0 ± 7.9 vs. 75.2 ± 8.5 μm, P = 0.009) were increased in CHF. Conclusions In CHF subjects, we observed hypertrophic remodelling of retinal arterioles indicative of similar changes of small resistance arteries in the systemic circulation. Microvascular structure and function assessed by SLDF may thereby represent a useful, non‐invasive method for monitoring of microvascular damage in patients with CHF and may offer innovative treatment targets for new CHF therapies.

Although photothermal therapy (PTT) has demonstrated its clinical value and adaptability, it still requires imaging guidance to motivate the development of precise and effective treatment. For PTT, high-resolution visualization of tumor microvasculature and accurate location of nanoparticles distribution are crucial for the therapeutic outcome. Here, a wavelength-switchable photoacoustic microscopy (PAM) was developed to noninvasively investigate the tumor microvasculature and the accumulation of nanoparticles for accurately guiding PTT and evaluating the therapeutic effect. In a tumor model, PAM was used to continuously monitor the tumor microenvironment in vivo, and the proportion of microvessels in tumor site was found increased by 10%, and the diameters of the draining veins were doubled on day 7. In addition, quantitative parameters such as tumor volume and vascular density can also be demonstrated by the PAM. Meanwhile, the concentration of Den-RGD/Cy7 at the tumor site reached its maximum at 8 h by PA mapping after intravenous injection, which was used to determine the optimal irradiation timing. After treatment, photoacoustic monitoring showed that PTT can precisely kill the tumors and minimize damage to surrounding normal tissues, which was consistent with the pathological slides. The experimental results proved that PAM can provide an auxiliary means for precision PTT.

The review discusses the development of optical coherence tomography with the function of angiography, focusing on its advantages, features, and prospects for the diagnosis of fundus pathologies.

Abstract Recent developments of organoids engineering and organ-on-a-chip microfluidic technologies have enabled the recapitulation of the major functions and architectures of microscale human tissue, including tumor pathophysiology. Nevertheless, there remain challenges in recapitulating the complexity and heterogeneity of tumor microenvironment. The integration of these engineering technologies suggests a potential strategy to overcome the limitations in reconstituting the perfusable microvascular system of large-scale tumors conserving their key functional features. Here, we review the recent progress of in vitro tumor-on-a-chip microfluidic technologies, focusing on the reconstruction of microvascularized organoid models to suggest a better platform for personalized cancer medicine.

Emerging evidence points to the beneficial role of greenspace exposure in promoting cardiovascular health. Most studies have evaluated such associations with conventional cardiovascular endpoints such as mortality, morbidity, or macrovascular markers. In comparison, the microvasculature, a crucial compartment of the vascular system where early subclinical signs of cardiovascular problems appear, has not been studied in association with greenspace exposure. The current study assessed the association between surrounding greenness and microvascular status, as assessed by retinal vessel diameters. This study included a sample of healthy adults (n = 114 and 18–65 years old) residing in three European cities [Antwerp (Belgium), Barcelona (Spain), and London (UK)]. The exposures to greenspace at the home and work/school locations were characterized as average surrounding greenness [normalized difference vegetation index (NDVI)] within buffers of 100 m, 300 m, and 500 m. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were calculated from fundus pictures taken at three different time points. We developed linear mixed-effect models to estimate the association of greenspace exposure with indicators of retinal microvasculature, adjusted for relevant individual and area-level covariates. We observed the most robust associations with CRVE. Higher levels of greenspace at work/school were associated with smaller retinal venules [(seasonal NDVI) 300m : 3.85, 95%CI -6.67,-1.03; 500m : 5.11, 95%CI -8.04, −2.18]. Findings for surrounding greenness and CRAE were not conclusive. Our study suggests an association of greenspace exposure with better microvascular status, specifically for retinal venules. Future research is needed to confirm our findings across different contextual settings. • Repeated-measurement design applied across three European cities. • Most robust associations with higher surrounding greenness and smaller venules. • Greenspace exposure was associated with retinal microvascular changes. [ABSTRACT FROM AUTHOR]

Leprosy, a chronic infectious disease, is associated with various nail changes. Its etiopathogenesis is multifaceted, with microvascular damage being crucial. Nail fold capillaroscopy (NFC) emerges as a novel tool for detecting early vascular deficits in leprosy. The study aimed to assess and provide a complete clinical characterization of NFC changes in leprosy patients. It is an observational cross-sectional study, done over a period of 1.5 year (January 2021 to august 2022) in a tertiary care hospital, encompassing 60 patients diagnosed with leprosy (18–60 years). After obtaining informed consent; detailed history, complete cutaneous and neurological examinations were conducted. All fingernails and toenails were examined for clinical changes. Subsequently, onychoscopy was performed using USB type of video-dermatoscope (Model AM7115MZT Dino-lite), a non-invasive tool. This was followed by NFC which was done for all fingernails and images were recorded by single operator, which were then assessed for quantitative and qualitive changes and statistical analysis was conducted using SPSS v20, with mean capillary density compared using Student's t -test, morphological change frequencies assessed by proportions, and group comparisons made using Chi-square or Fischer exact tests, with a significance threshold of p < 0.05. Among the 60 patients, 39 were in the lepromatous group, which included both borderline lepromatous (BL) and lepromatous leprosy (LL) patients, and 17 were in the tuberculoid group, which included borderline tuberculoid (BT) leprosy patients; 23.3 % had Type 1 reactions, and 18.3 % had Type 2 reactions. Nail fold capillaroscopy (NFC) showed microvasculature changes in 93.3 % of patients. The average capillary density was 6.8 ± 1.5 capillaries per mm, with the lepromatous group having a lower density (6.5 ± 1.09) compared to the tuberculoid group (7.0 ± 0.86). The most common NFC changes in the tuberculoid group were tortuous capillaries (70 %), capillary dropouts, and dilated capillaries (both 64.7 %). In the lepromatous group, capillary dropouts (82 %) were most frequent, followed by tortuous (69 %), receding (69 %), and dilated capillaries (66 %). A dilated and prominent subpapillary plexus was more common in the lepromatous group (35 %, p = 0.04). Patients with trophic changes in the lepromatous group had more capillary dropouts and bizarre capillaries. Capillary dropouts, dilated capillaries, and visible subpapillary venous plexus were more prevalent in patients with Type 2 reactions. NFC changes are prevalent in both tuberculoid and lepromatous leprosy, which may be an indicator of peripheral vascular compromise and trophic changes, especially in lepromatous leprosy. NFC can be an auxiliary tool for detecting microvascular abnormalities in leprosy patients. • The study supports the use of NFC as a non-invasive, practical tool for early detection of microvascular damage in leprosy patients. • NFC revealed microvasculature changes in 93.3% of leprosy patients, indicating significant impact of leprosy on microvascular system. • Average capillary density was notably lower in lepromatous group compared to tuberculoid group, suggesting greater microvascular damage. • Dilated and prominent subpapillary plexus was significantly more common in lepromatous group indicating a potential marker for severe vascular involvement. • Patients in lepromatous group with trophic changes exhibited more frequent capillary dropouts and bizarre capillaries, highlighting relationship between microvascular changes and trophic ulcerations. [ABSTRACT FROM AUTHOR]

Objective: To assess the potential therapeutic role of exercise on health-related quality of life, assessed by the Pediatric Outcomes Data Collection Instrument (PODCI), coronary flow reserve (CFR), cardiac function, cardiorespiratory fitness, and inflammatory and cardiac blood markers in multisystemic inflammatory syndrome in children (MIS-C) patients. Methods: This is a case series study of a 12-wk, home-based exercise intervention in children and adolescents after MIS-C diagnosis. From 16 MIS-C patients followed at our clinic, 6 were included (age: 7–16 years; 3 females). Three of them withdrew before the intervention and served as controls. The primary outcome was health-related quality of life, assessed PODCI. Secondary outcomes were CFR assessed by 13N-ammonia PET-CT imaging, cardiac function by echocardiography, cardiorespiratory fitness, and inflammatory and cardiac blood markers. Results: In general, patients showed poor health-related quality of life, which seemed to be improved with exercise. Additionally, exercised patients showed improvements in coronary flow reserve, cardiac function, and aerobic conditioning. Non-exercised patients exhibited a slower pattern of recovery, particularly in relation to health-related quality of life and aerobic conditioning. Conclusions: Our results suggest that exercise may play a therapeutic role in the treatment of post-discharge MIS-C patients. As our design does not allow inferring causality, randomized controlled trials are necessary to confirm these preliminary findings.

Background: Current assessment standards in chronic limb-threatening ischemia (CLTI) focus on macrovascular function while neglecting the microcirculation. Multispectral near-infrared spectroscopy (NIRS) provides hemodynamic characteristics of the microcirculation (i.e., capillaries) and may be a powerful tool for monitoring CLTI and preventing extremity loss. The aims of this study were to (1) investigate the effects of lower limb revascularization on the microcirculation and (2) determine if macrovascular and microvascular assessments correlate. Methods: An observational, retrospective cohort study of 38 endovascular interventions in 30 CLTI subjects was analyzed pre- and post-intervention for arterial Doppler acceleration times (AcT; macrovascular) and NIRS metrics (microvascular). Pre-intervention ankle-brachial index (ABI) was also analyzed. Results: AcT significantly decreased (p = 0.009) while oxyhemoglobin (HbO) significantly increased (p < 0.04) after endovascular intervention, indicating treatment efficacy. However, macrovascular measurements (ABI, AcT) and NIRS metrics of oxygenation and perfusion did not correlate (p > 0.06, r2 < 0.15, n = 23) indicating that macro- and microvascular assessment are not congruent. Conclusion: These findings suggest that macrovascular and microvascular assessments can determine interventional efficacy in their corresponding vasculature. Their lack of correlation, however, suggests the need for simultaneous assessment as independent use may cause diagnostic information to be missed. [ABSTRACT FROM AUTHOR]

Background: The retina and brain share similar neuronal and microvascular features. We aimed to investigate the retinal thickness and microvasculature in patients with thalamic infarcts compared with control participants. Material and methods: Swept-source optical coherence tomography (SS-OCT) was used to image the macular thickness (retinal nerve fiber layer, RNFL; ganglion cell-inner plexiform layer, GCIP), while OCT angiography was used to image the microvasculature (superficial vascular plexus, SVP; intermediate capillary plexus, ICP; deep capillary plexus, DCP). Inbuilt software was used to measure the macular thickness (µm) and microvascular density (%). Lesion volumes were quantitively assessed based on structural magnetic resonance images. Results: A total of 35 patients with unilateral thalamic infarction and 31 age–sex-matched controls were enrolled. Compared with control participants, thalamic infarction patients showed a significantly thinner thickness of RNFL (p < 0.01) and GCIP (p = 0.02), and a lower density of SVP (p = 0.001) and ICP (p = 0.022). In the group of patients, ipsilateral eyes showed significant reductions in SVP (p = 0.033), RNFL (p = 0.01) and GCIP (p = 0.043). When divided into three groups based on disease duration (<1 month, 1–6 months, and >6 months), no significant differences were found among these groups. After adjusting for confounders, SVP, ICP, DCP, RNFL, and GCIP were significantly correlated with lesion volume in patients. Conclusions: Thalamic infarction patients showed significant macular structure and microvasculature changes. Lesion size was significantly correlated with these alterations. These findings may be useful for further research into the clinical utility of retinal imaging in stroke patients, especially those with damage to the visual pathway. [ABSTRACT FROM AUTHOR]

For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain's principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC's roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the changes in retinal microvasculature in eyes with anterior uveitis (AU) using optical coherence tomography angiography. Methods: Foveal avascular zone (FAZ) of superficial capillary plexus (SCP) and deep capillary plexus (DCP), vessel density (VD) of SCP, DCP, and choriocapillaris, and central macular thickness (CMT) and central foveal thickness (CFT) were calculated from 34 healthy and 41 uveitic eyes. The parameters were compared between the two groups. Results: The deep FAZ was significantly smaller in the eyes with AU during the attack than after recovery and the control group (p = 0.001 and p = 0.003, respectively). The VD in deep capillary plexus (DCP) in eyes with AU during the attack was significantly higher than the control group (p = 0.048). The VD in the foveal sector of DCP in eyes with AU during the attack and after recovery was significantly higher than the control group (p = 0.001 and p = 0.031, respectively). There was no significant difference regarding CMT, CFT, VDs of each segment and each sector, and superficial and deep FAZ between eyes with first uveitis attack and those with recurrent uveitis during the attack and after recovery (p > 0.05). Conclusion: The results of this study show that there is a reduction in the FAZ and an increase in the VD of the DCP of the retina during active AU, and these findings are reversible. Acute AU may affect the macular microvasculature, which is usually temporary, especially in the DCP. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a multifactorial and complex disease. Our knowledge of the cellular and genetic basis of NEC have expanded considerably as new molecular mechanisms have been identified. This article will focus on the current understanding of the molecular pathogenesis of NEC with a focus on the inflammatory, immune, infectious, and genetic mechanisms that drive disease development. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?It is valuable to be able to monitor disease‐ or treatment‐related changes in the microcirculation. Laser Doppler flowmetry with local heating allows non‐invasive monitoring of the skin microcirculation and its ability to vasodilate. Does reactive hyperaemia augment the increase in skin blood flow elicited by local heating?What is the main finding and its importance?The addition of reactive hyperaemia to local heating results in greater vasodilatation than heating alone. Thus, reactive hyperaemia can augment local heat‐induced hyperaemia in the skin. The skin circulation has been proposed as a model of generalized microvascular function that could be monitored non‐invasively using laser Doppler flowmetry (LDF). The response to heat hyperaemia (HH) is commonly used to monitor disease‐ or treatment‐related changes in microvascular function. We hypothesized that reactive hyperaemia would augment the increase in skin blood flow elicited by local heating. Fourteen healthy young adults were subjected to three different conditions: reactive hyperaemia (RH; skin temperature controlled at 33°C), heat hyperaemia (HH; 42°C held for 40 min) and HH+RH. Two Peltier‐controlled thermomodules with LDF probes were placed on the right forearm to monitor skin blood flow continuously. A cuff was placed on the right upper arm to elicit RH by inflation to 220 mmHg for 5 min. This procedure was performed with the skin temperature at 33°C and again after 40 min of local heating to 42°C. Beat‐by‐beat mean arterial pressure (MAP) obtained by a photoplethysmographic sensor on the middle finger of the left hand allowed calculation of cutaneous vascular conductance (CVC) as LDF/MAP. Both HH and RH increased LDF (P < 0.0001 and P < 0.0001, respectively) and CVC (P = 0.0001 and P < 0.0001, respectively) above baseline values. The LDF and CVC values were significantly higher during HH+RH when compared with RH or HH alone (P < 0.0001). In summary, HH+RH resulted in greater vasodilatation when compared with HH or RH alone. These results indicate that RH can augment local heat‐induced hyperaemia in the skin. [ABSTRACT FROM AUTHOR]

Background: The microvasculature is a target organ for the early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES‐1 inhibition and concomitant reduction of PGE2 in vascular beds are of interest. Experimental Approach The effects of mPGES‐1 inhibition on constriction and relaxation of resistance arteries (diameter: 100–400 μm) from patients with end stage kidney disease (ESKD) and controls (Non‐ESKD) were studied using wire‐myography in combination with immunological and mass‐spectrometry based analyses. Key Results: Inhibition of mPGES‐1 in arteries from ESKD patients and Non‐ESKD controls significantly reduced adrenergic vasoconstriction, which was unaffected by the COX‐2 inhibitors NS‐398 and Etoricoxib, or by the COX‐1/COX‐2 inhibitor Indomethacin tested in Non‐ESKD controls. However, a significant increase of acetylcholine‐induced dilatation was observed for mPGES‐1 inhibition. In IL‐1β treated arteries, inhibition of mPGES‐1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX‐2 inhibition blocked the formation of both prostaglandins. Blockade of PGI2 signalling with an IP receptor antagonist did not restore the reduced adrenergic constriction, neither did blocking PGE2‐EP4 or signalling through PPARγ. A biphasic effect was observed for PGE2, inducing dilatation at nanomolar and constriction at micromolar concentrations. Immunohistochemistry demonstrated expression of mPGES‐1, COX‐1, PGIS, weak expression for COX‐2, as well as receptor expression for PGE2 (EP1–4), thromboxane (TP) and PGI2 (IP) in ESKD and Non‐ESKD. Conclusion: Our study demonstrates vasodilating effects following mPGES‐1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 are involved. [ABSTRACT FROM AUTHOR]

Remodeling of tissue microvasculature commonly promotes neoplastic growth; however, there is no imaging modality in oncology yet that noninvasively quantifies microvascular changes in clinical routine. Although blood capillaries cannot be resolved in typical magnetic resonance imaging (MRI) measurements, their geometry and distribution influence the integral nuclear magnetic resonance (NMR) signal from each macroscopic MRI voxel. We have numerically simulated the expected transverse relaxation in NMR voxels with different dimensions based on the realistic microvasculature in healthy and tumor‐bearing mouse brains (U87 and GL261 glioblastoma). The 3D capillary structure in entire, undissected brains was acquired using light sheet fluorescence microscopy to produce large datasets of the highly resolved cerebrovasculature. Using this data, we trained support vector machines to classify virtual NMR voxels with different dimensions based on the simulated spin dephasing accountable to field inhomogeneities caused by the underlying vasculature. In prediction tests with previously blinded virtual voxels from healthy brain tissue and GL261 tumors, stable classification accuracies above 95% were reached. Our results indicate that high classification accuracies can be stably attained with achievable training set sizes and that larger MRI voxels facilitated increasingly successful classifications, even with small training datasets. We were able to prove that, theoretically, the transverse relaxation process can be harnessed to learn endogenous contrasts for single voxel tissue type classifications on tailored MRI acquisitions. If translatable to experimental MRI, this may augment diagnostic imaging in oncology with automated voxel‐by‐voxel signal interpretation to detect vascular pathologies. [ABSTRACT FROM AUTHOR]

Introduction. Ocular microvascular changes can be related to kidney deterioration in chronic kidney disease (CKD). We aimed to identify the association between retino-choroidal parameters and kidney deterioration in diabetics and non-diabetics. Methods. The study group consisted of CKD patients (cross-sectional study) with arterial hypertension with different stages of CKD. Complete eye examination was completed with optical coherence tomography angiography (OCTA) scans of the macular region. According to the value of glomerular filtration rate (GFR) and albuminuria, patients were divided into groups: low GFR (60ml/min) and CKD patients without albuminuria and CKD with micro or macroalbuminuria. Results. One hundred and six eyes of 106 chronic kidney disease patients were evaluated. The mean retinal thickness in GFR 60 ml/min group was 274,36±10,77 μ. OCTA showed lower deep vascular density (DVD ) in CKD with albuminuria versus CKD without albuminuria group (p < 0.001). Albuminuria was inversely related to choroidal and retinal thickness measures of superficial (SVD) and DVD . Conclusions. CKD is associated with retinal diluting and decreasing kidney function with reduction of retinal and choroidal vascular density.

Blood vessels are ubiquitous in the human body and play essential roles not only in the delivery of vital oxygen and nutrients but also in many disease implications and drug transportation. Although fabricating in vitro blood vessels has been greatly facilitated through various microfluidic organ-on-chip systems, most platforms that are used in the laboratories suffer from a series of laborious processes ranging from chip fabrication, optimization, and control of physiologic flows in micro-channels. These issues have thus limited the implementation of the technique to broader scientific communities that are not ready to fabricate microfluidic systems in-house. Therefore, we aimed to identify a commercially available microfluidic solution that supports user custom protocol developed for microvasculature-on-a-chip (MVOC). The custom protocol was validated to reliably form a smooth and functional blood vessel using a viscous fingering (VF) technique. Using VF technique, the unpolymerized collagen gel in the media channels was extruded by less viscous fluid through VF passive flow pumping, whereby the fluid volume at the inlet and outlet ports are different. The different diameters of hollow tubes produced by VF technique were carefully investigated by varying the ambient temperature, the pressure of the passive pump, the pre-polymerization time, and the concentration of collagen type I. Subsequently, culturing human umbilical vein endothelial cells inside the hollow structure to form blood vessels validated that the VF-created structure revealed a much greater permeability reduction than the vessel formed without VF patterns, highlighting that a more functional vessel tube can be formed in the proposed methodology. We believe the current protocol is timely and will offer new opportunities in the field of in vitro MVOC.

PurposeAs the human immunodeficiency virus (HIV) pandemic is far from over, whether there are subclinical macular changes in HIV-positive patients is something that should not be overlooked. We aimed to apply optical coherence tomography angiography (OCTA) to assess the macular structure and microvasculature changes in patients with HIV without infectious retinopathy.MethodsHIV-positive and -negative participants were included and classified into three groups: HIV-negative, HIV-positive, and HIV-positive with microvasculopathy. OCTA parameters regarding macular structure and microvasculature were analyzed.ResultsCompared with the HIV-negative group, the superficial retinal vessel density (VD) in the parafovea sectors and the whole Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and the choroidal vascularity index (CVI) in the whole ETDRS grid were significantly decreased in the HIV-positive and HIV-positive with microvasculopathy groups (p < 0.05). No differences were found in OCTA parameters between the HIV-positive and HIV-positive with microvasculopathy groups. Retinal, retinal nerve fiber layer-ganglion cell layer-inner plexiform layer (RNFL-GCL-IPL), RNFL, GCL-IPL, and INL thickness showed a negative association with the duration of HIV diagnosis or antiretroviral therapy (ART) (all p < 0.05). All OCTA microvasculature parameters showed no association with HIV-related clinical variables (all p > 0.05).ConclusionsSubclinical macular changes existed in HIV-infected patients without clinical infectious retinopathy. Substructures from inner retinal layers might be associated with HIV infection or ART duration.

BackgroundCerebral microhemorrhages (CMH) are tiny deposits of blood degradation products in the brain and are pathological substrates of cerebral microbleeds. The existing CMH animal models are β-amyloid-, hypoxic brain injury-, or hypertension-induced. Recent evidence shows that CMH develop independently of hypoxic brain injury, hypertension, or amyloid deposition and CMH are associated with normal aging, sepsis, and neurodegenerative conditions. One common factor among the above pathologies is inflammation, and recent clinical studies show a link between systemic inflammation and CMH. Hence, we hypothesize that inflammation induces CMH development and thus, lipopolysaccharide (LPS)-induced CMH may be an appropriate model to study cerebral microbleeds.MethodsAdult C57BL/6 mice were injected with LPS (3 or 1 mg/kg, i.p.) or saline at 0, 6, and 24 h. At 2 or 7 days after the first injection, brains were harvested. Hematoxylin and eosin (H&E) and Prussian blue (PB) were used to stain fresh (acute) hemorrhages and hemosiderin (sub-acute) hemorrhages, respectively. Brain tissue ICAM-1, IgG, Iba1, and GFAP immunohistochemistry were used to examine endothelium activation, blood-brain barrier (BBB) disruption, and neuroinflammation. MRI and fluorescence microscopy were used to further confirm CMH development in this model.ResultsLPS-treated mice developed H&E-positive (at 2 days) and PB-positive (at 7 days) CMH. No surface and negligible H&E-positive CMH were observed in saline-treated mice (n = 12). LPS (3 mg/kg; n = 10) produced significantly higher number, size, and area of H&E-positive CMH at 2 days. LPS (1 mg/kg; n = 9) produced robust development of PB-positive CMH at 7 days, with significantly higher number and area compared with saline (n = 9)-treated mice. CMH showed the highest distribution in the cerebellum followed by the sub-cortex and cortex. LPS-induced CMH were predominantly adjacent to cerebral capillaries, and CMH load was associated with indices of brain endothelium activation, BBB disruption, and neuroinflammation. Fluorescence microscopy confirmed the extravasation of red blood cells into the brain parenchyma, and MRI demonstrated the presence of cerebral microbleeds.ConclusionsLPS produced rapid and robust development of H&E-positive (at 2 days) and PB-positive (at 7 days) CMH. The ease of development of both H&E- and PB-positive CMH makes the LPS-induced mouse model suitable to study inflammation-induced CMH.

PurposeLoss of photoreceptor cells is associated with retinal vascular degeneration in retinitis pigmentosa, whereas the presence of photoreceptor cells is implicated in vascular degeneration in diabetic retinopathy. To investigate how both the absence and presence of photoreceptors could damage the retinal vasculature, we compared two mouse models of photoreceptor degeneration (opsin-/- and RhoP23H/P23H ) and control C57Bl/5J mice, each with and without diabetes.MethodsRetinal thickness, superoxide, expression of inflammatory proteins, ERG and optokinetic responses, leukocyte cytotoxicity, and capillary degeneration were evaluated at 1 to 10 months of age using published methods.ResultsRetinal photoreceptor cells degenerated completely in the opsin mutants by 2 to 4 months of age, and visual function subsided correspondingly. Retinal capillary degeneration was substantial while photoreceptors were still present, but slowed after the photoreceptors degenerated. Diabetes did not further exacerbate capillary degeneration in these models of photoreceptor degeneration, but did cause capillary degeneration in wild-type animals. Photoreceptor cells, however, did not degenerate in wild-type diabetic mice, presumably because the stress responses in these cells were less than in the opsin mutants. Retinal superoxide and leukocyte damage to retinal endothelium contributed to the degeneration of retinal capillaries in diabetes, and leukocyte-mediated damage was increased in both opsin mutants during photoreceptor cell degeneration.ConclusionsPhotoreceptor cells affect the integrity of the retinal microvasculature. Deterioration of retinal capillaries in opsin mutants was appreciable while photoreceptor cells were present and stressed, but was less after photoreceptors degenerated. This finding proves relevant to diabetes, where persistent stress in photoreceptors likewise contributes to capillary degeneration.

Cranial irradiation used to control CNS malignancies can also disrupt the vasculature and impair neurotransmission and cognition. Here we describe two distinct methodologies for quantifying early and late radiation injury in CNS microvasculature. Intravascular fluorescently labeled lectin was used to visualize microvessels in the brain of the irradiated mouse 2 days post exposure and RECA-1 immunostaining was similarly used to visualize microvessels in the brain of the irradiated rat 1-month post exposure. Confocal microscopy, image deconvolution and 3-dimensional rendering methods were used to define vascular structure in a ∼4 × 10(7) μm(3) defined region of the brain. Quantitative analysis of these 3D images revealed that irradiation caused significant short- and long-term reductions in capillary density, diameter and volume. In mice, irradiation reduced mean vessel volume from 2,250 to 1,470 μm(3) and mean vessel diameter from 5.0 to 4.5 μm, resulting in significant reductions of 34% and 10%, in the hippocampus respectively. The number of vessel branch points and area was also found to also drop significantly in mice 2 days after irradiation. For rats, immunostaining revealed a significant, three-fold drop in capillary density 1 month after exposure compared to controls. Such radiation-induced disruption of the CNS microvasculature may be contributory if not causal to any number of neurocognitive side effects that manifest in cancer patients following cranial radiotherapy. This study demonstrates the utility of two distinct methodologies for quantifying these important adverse effects of radiotherapy. Environ. Mol. Mutagen. 57:341-349, 2016. © 2016 Wiley Periodicals, Inc.

Insulin increases muscle microvascular perfusion, which contributes to its metabolic action in muscle, but this action is impaired in obesity. Metformin improves endothelial function beyond its glucose lowering effects. We aim to examine whether metformin could prevent microvascular insulin resistance and endothelial dysfunction during the development of obesity. Adult male rats were fed a high-fat diet (HFD) with or without simultaneous metformin administration for either 2 or 4 wk. Insulin's metabolic and microvascular actions were determined using a combined euglycemic-hyperinsulinemic clamp and contrast-enhanced ultrasound approach. Compared with chow-fed controls, HFD feeding increased body adiposity without excess body weight gain, and this was associated with a marked decrease in insulin-mediated whole body glucose disposal and abolishment of insulin-induced muscle microvascular recruitment. Simultaneous administration of metformin fully rescued insulin-induced muscle microvascular recruitment as early as 2 wk and normalized insulin-mediated whole body glucose disposal at week 4. The divergent responses between insulin's microvascular and metabolic actions seen at week 2 were accompanied with reduced endothelial oxidative stress and vascular inflammation, and improved endothelial function and vascular insulin signaling in metformin-treated rats. In conclusions, metformin could prevent the development of microvascular insulin resistance and endothelial dysfunction by alleviating endothelial oxidative stress and vascular inflammation during obesity development. [ABSTRACT FROM AUTHOR]

Purpose: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long‐term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). Methods: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932–1933) and the WWII (1941–1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942–1945. Results: During the Holodomor and WWII, perinatal famine was associated with a 1.76‐fold (p = 0.019) and 3.02‐fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66‐fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). Conclusion: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is associated with coronary microvascular dysfunction, which is thought to contribute to compromised diastolic function, ultimately culminating in heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms remain incompletely understood, and no early diagnostics are available. We sought to gain insight into biomarkers and potential mechanisms of microvascular dysfunction in obese mouse (db/db) and lean rat (Goto-Kakizaki) pre-clinical models of T2D-associated diastolic dysfunction. Methods: The microRNA (miRNA) content of circulating extracellular vesicles (EVs) was assessed in T2D models to identify biomarkers of coronary microvascular dysfunction/rarefaction. The potential source of circulating EV-encapsulated miRNAs was determined, and the mechanisms of induction and the function of candidate miRNAs were assessed in endothelial cells (ECs). Results: We found an increase in miR-30d-5p and miR-30e-5p in circulating EVs that coincided with indices of coronary microvascular EC dysfunction (i.e., markers of oxidative stress, DNA damage/senescence) and rarefaction, and preceded echocardiographic evidence of diastolic dysfunction. These miRNAs may serve as biomarkers of coronary microvascular dysfunction as they are upregulated in ECs of the left ventricle of the heart, but not other organs, in db/db mice. Furthermore, the miR-30 family is secreted in EVs from senescent ECs in culture, and ECs with senescent-like characteristics are present in the db/db heart. Assessment of miR-30 target pathways revealed a network of genes involved in fatty acid biosynthesis and metabolism. Over-expression of miR-30e in cultured ECs increased fatty acid β-oxidation and the production of reactive oxygen species and lipid peroxidation, while inhibiting the miR-30 family decreased fatty acid β-oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to down-regulate the expression of eNOS, a key regulator of microvascular and cardiomyocyte function. Finally, knock-down of the miR-30 family in db/db mice decreased markers of oxidative stress and DNA damage/senescence in the microvascular endothelium. Conclusions: MiR-30d/e represent early biomarkers and potential therapeutic targets that are indicative of the development of diastolic dysfunction and may reflect altered EC fatty acid metabolism and microvascular dysfunction in the diabetic heart. [ABSTRACT FROM AUTHOR]

Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance have not been defined. Eleven subjects with nondiabetic metabolic syndrome were studied four times (before and after 12 wk of treatment with placebo or metformin) using a crossover design, with an 8-wk washout interval between treatments. On each occasion, we measured three indices of large artery function [pulse wave velocity (PWV), radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flowmediated dilation-FMD)] as well as muscle microvascular perfusion [contrast-enhanced ultrasound (CEU)] before and at 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. Metformin decreased body mass index (BMI), fat weight, and % body fat (P < 0.05, each), however, placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate, P < 0.01), PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin P < 0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (P < 0.02 for each) but not after metformin. Shortterm metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhanced radial pulse wave properties consistent with relaxation of smaller arterioles. [ABSTRACT FROM AUTHOR]

Cardiovascular (CV) disease (CVD) is the main cause of death around the world, and assessing a patient's CV risk factors (CVRF) can play a major role in its prevention. Since it has been shown that retinal vascular alterations may reflect several systemic processes such as CVRF, we conducted a systematic review in order to summarize which ocular microvasculature changes can be found using Optical Coherence Tomography Angiography (OCTA) in patients without ocular diseases and with systemic pathologies/conditions that affect the CV system when compared to healthy subjects. We searched on online databases, namely PubMed, Scopus, Cochrane and Web of Science, and obtained additional studies through citation tracking. Case reports and review articles were excluded. A total of 47 articles were included in our review. We describe that patients with hypertension, diabetes mellitus, kidney disease, preeclampsia, coronary artery disease, carotid artery stenosis and obstructive sleep apnoea syndrome have, in general, lower retinal and choroidal Vessel Density (VD) and Length (VL), as well as an increased foveal avascular zone area and perimeter. Additionally, several characteristics and/or conditions in healthy subjects, such as smoking status, hyper or hypoxia conditions, race, among others, are also related to ocular vascular changes and should be accounted for. We concluded that OCTA could be a useful tool to assess a patient's CV risk profile in a non‐invasive way, possibly integrating the diagnostic and prognostic algorithms of the most prevalent CV diseases in the future. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility of intravoxel incoherent motion (IVIM) in assessing blood–brain barrier (BBB) integrity and microvasculature in tumoral tissue of glioma patients. Methods: Images from 8 high-grade and 4 low-grade glioma patients were acquired on a 3 T MRI scanner. Acquisition protocol included pre- and post-contrast T1- and T2-weighted imaging, FLAIR, dynamic susceptibility contrast (DSC), and susceptibility-weighted imaging (SWI). In addition, IVIM was acquired with 15 b-values and fitted under the non-negative least square (NNLS) model to output the diffusion (D) and pseudo-diffusion (D*) coefficients, perfusion fraction (f), and f times D* (fD*) maps. Results: IVIM perfusion-related maps were sensitive to (1) blood flow and perfusion alterations within the microvasculature of brain tumors, in agreement with intra-tumoral susceptibility signal (ITSS); (2) enhancing areas of BBB breakdown in agreement with DSC maps as well as areas of BBB abnormality that was not detected on DSC maps; (3) enhancing perfusion changes within edemas; (4) detecting early foci of increased perfusion within low-grade gliomas. Conclusion: The results suggest IVIM may be a promising approach to delineate tumor extension and progression in size, and to predict histological grade, which are clinically relevant information that characterize tumors and guide therapeutic decisions in patients with glioma. [ABSTRACT FROM AUTHOR]

Advanced age is related to functional alterations of human vasculature, but erectile dysfunction precedes systemic manifestations of vascular disease. The current study aimed to simultaneously evaluate the influence of aging on vascular function (relaxation and contraction responses) in systemic human vascular territories: aorta (HA) and resistance mesenteric arteries (HMA) and human corpus cavernosum (HCC) and penile resistance arteries (HPRA). Associations of oxidative stress and inflammation circulating biomarkers with age and functional responses were also determined. Vascular specimens were obtained from 76 organ donors (age range 18–87). Four age-groups were established: < 40, 40–55, 56–65 and > 65 years old. Increasing age was associated with a decline in endothelium-dependent relaxation induced by BK in HMA (r = -0.597, p = 0.0001), or by ACh in HCC (r = -0.505, p = 0.0022), and HPRA (r = -0.601, p = 0.0012). Significant impairment was detected at > 65 years old in HMA but earlier in penile vasculature (> 55 years old). Age-related reduction to H2O2-vasodilatory response started before in HCC (56–65 years old) than in HA (> 65 years old). In contrast to relaxation responses, aging-related hypercontractility to adrenergic stimulation was homogeneous: contractions significantly increased in subjects > 55 years old in all tested vessels. Although not significantly age related, circulating levels of ADMA (r = -0.681, p = 0.0052) and TNF-α (r = -0.537, p = 0.0385) were negatively correlated with endothelial vasodilation in HMA but not in HCC or HPRA. Penile vasculature exhibits an early impairment of endothelium-dependent and H2O2-induced vasodilations when compared to mesenteric microcirculation and aorta. Therefore, functional susceptibility of penile vasculature to the aging process may account for anticipation of erectile dysfunction to systemic manifestations of vascular disease. [ABSTRACT FROM AUTHOR]

Background: Skin microvasculature changes are crucial in psoriasis development and correlate with perfusion. The noninvasive Handheld Perfusion Imager (HAPI) examines microvascular skin perfusion in large body areas using laser speckle contrast imaging (LSCI). Objectives: To (i) assess whether increased perilesional perfusion and perfusion inhomogeneity are predictors for expansion of psoriasis lesions and (ii) assess feasibility of the HAPI system in a mounted modality. Methods: In this interventional pilot study in adults with unstable plaque psoriasis, HAPI measurements and color photographs were performed for lesions present on one body region at week 0, 2, 4, 6 and 8. The presence of increased perilesional perfusion and perfusion inhomogeneity was determined. Clinical outcome was categorized as increased, stable or decreased lesion surface between visits. Patient feedback was collected on a 10‐point scale. Results: In total, 110 lesions with a median follow‐up of 6 (IQR 6.0) weeks were assessed in 6 patients with unstable plaque psoriasis. Perfusion data was matched to 281 clinical outcomes after two weeks. A mixed multinomial logistic regression model revealed a predictive value of perilesional increased perfusion (OR 9.90; p < 0.001) and perfusion inhomogeneity (OR 2.39; p = 0.027) on lesion expansion after two weeks compared to lesion stability. HAPI measurements were considered fast, patient‐friendly and important by patients. Conclusion: Visualization of increased perilesional perfusion and perfusion inhomogeneity by noninvasive whole field LSCI holds potential for prediction of psoriatic lesion expansion. Furthermore, the HAPI is a feasible and patient‐friendly tool. [ABSTRACT FROM AUTHOR]