Microvascular Vessel Research Articles

Endoscopic characteristics to differentiate SSLs and microvesicular hyperplastic polyps from goblet cell-rich hyperplastic polyps.

Background and study aims Among colorectal serrated polyps (SPs), sessile serrated lesions (SSLs) and hyperplastic polyps (HPs) have a similar endoscopic appearance. However, the endoscopic distinctions between those two categories, microvesicular HPs (MVHPs) and goblet cell-rich HPs (GCHPs), are not well understood. Therefore, we compared the endoscopic features of SSLs, MVHPs, and GCHPs. Methods This retrospective, cross-sectional study was conducted at the Toyoshima Endoscopy Clinic. We examined polyp size, location, Paris classification type, mucus cap, indistinct border, expanded crypt opening, varicose microvascular vessels, and JNET classification type. Multivariable analysis of each endoscopic finding using a binomial logistic regression model determined the factors that predicted SP histology. Results A total of 670 SPs were enrolled in this study, comprising 159 SSLs, 361 MVHPs, and 150 GCHPs. On comparing the SSL + MVHP group and the GCHP group, a mucus cap (partial regression coefficient 1.705), expanded crypt opening (1.828), and varicose microvascular vessels (1.270) were more often observed in the SSL + MVHP group compared with the GCHP group. In the comparison between MVHPs and GCHPs, a mucus cap (1.564), expanded crypt opening (1.802), and varicose microvascular vessels (1.288) were more often found in MVHPs in contrast to GCHPs. When comparing SSLs and MVHPs, SSLs were more likely to be in the proximal colon (0.662) and were larger (0.198) than the MVHPs. No significant differences were observed in other endoscopic findings. Conclusions SSLs and MVHPs have endoscopic appearances that differ from those of GCHPs. Considering MVHPs and GCHPs as distinct entities may aid in endoscopic diagnosis of SPs.

Functional improvement of non-infarct related coronary artery stenosis by extensive LDL-C reduction with a PCSK9 antibody: the FITTER trial, microvascular function analysis

Abstract Background Atherosclerosis and microvascular dysfunction are closely linked. Moreover, impaired microvascular function is strongly associated with increased risk on major adverse cardiac events. In patients presenting with acute coronary syndrome (ACS), microvascular function is reduced. PCSK9-inhibitors have shown to reduce plaque burden and lipid load in epicardial vessels and might exhibit similar results on microvascular vessels, thereby improving microvascular function. The FITTER trial offers the unique opportunity to test this hypothesis. Methods The FITTER trial is a multi-center, randomized, double blind, placebo controlled clinical trial for patients presenting with ACS and multi-vessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) measurement of non-infarct related artery (non-IRA) lesions was performed. Patients with intermediate, non-critical lesions (FFR: 0.67-0.85) were included in this trial. For exploratory purpose, additional physiological assessment of the non-IRA included coronary flow reserve (CFR) and microvascular resistance index (IMR) measurements. Microvascular function was evaluated using a pressure- and temperature-sensitive guidewire and a bolus thermodilution method. Participants were randomized and treated for 12 weeks with either evolocumab or placebo in addition to high-intensity statin therapy. Staged reevaluation was done at 12 weeks. After repeated physiology testing, PCI was performed if deemed necessary. Pre-defined exploratory analysis includes the absolute and relative difference in change between CFR and IMR from baseline to follow up in the non-IRA. PCSK9 inhibition might result in a relatively larger increase of CFR and larger decrease of IMR. Results Between March 2020 and August 2023, a total of 150 patients were included in the trial. In 61 patients (88.5% male, age 65.3 ± 9.1 years, 23.0% STEMI, 70.5% non-STEMI, 6.6% UAP) successful baseline and follow-up measurements of microvascular function were performed. Complete results will be available at the beginning of March 2024. The primary- and secondary endpoints will be submitted for late-breaking clinical trials selection. The results of this abstract will include a per vessel analysis of coronary artery microvascular function. Conclusion The FITTER trial will provide new insights on the potential of extensive LDL-C reduction with a PCSK9 antibody on microvascular coronary artery function in patients presenting with ACS and MVD.

Prognostic outcome of ACS in HTX patients after PCI

Abstract Background Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide, particularly in countries with limited access to healthcare [1,2]. Acute coronary syndrome is a collective term for several clinical conditions resulting from narrowing or occlusion of the coronary arteries [3,4]. Another group of patients affected by cardiovascular disease are those who have undergone heart transplantation. Long-term survival after transplantation is limited by cardiac allograft vasculopathy, a condition that affects the coronary arteries of the donor heart and causes diffuse narrowing [5,6]. Our retrospective analysis aims to compare the prognostic outcomes of HTX patients with ACS who underwent PCI with patients without a history of HTX. Results A total of 3194 patients with ACS were enrolled, of whom 1.16% (37) had a previous heart transplant. Patients with prior transplantation were on average younger (52.54 ± 15.13 vs. 69.76 ± 12.16, p < 0.001), had less dyspnea (p < 0.001) and a different distribution of ACS types (p < 0.001), as shown in Figure 1. There were no differences in sex (p = 0.287), BMI (p = 0.123), hypertension (p = 0.557), diabetes mellitus (p = 0.188) and previous myocardial infarction (p = 0.681). The majority of HTX patients were diagnosed with ISHLT CAV III (58.54%) and the average time to PCI was 12 years after transplantation. Multi-vessel disease was more common in HTX patients (p < 0.001). In addition, calcification was less frequent in the HTX group than in the control group (p < 0.001), and the lesion morphology was more diffuse in the HTX group (p < 0.001). On the other hand, there was no difference in the distribution of target vessels (p = 0.424), with the left anterior descending being the most frequently treated coronary artery, followed by the left circumflex and right coronary arteries. HTX patients received more stents (p < 0.001). There was also a difference in post-procedural TIMI flow achieved (p = 0.047), with less TIMI 3 flow achieved after PCI in the HTX group (80% vs. 93.59%). Technical success was less likely to be achieved in the HTX group (62.50% vs. 96.29%, p < 0.001), as was procedural success (47.06% vs. 89.68%, p < 0.001). There was no difference in the incidence of complications, which include perforation and bleeding (p = 0.284). All-cause mortality at three years (39.02% vs. 17.50%, p < 0.001), stroke (7.32% vs. 1.59%, p = 0.035) and myocardial infarction (p = 0.026) were higher in the HTX group. Over a period of three years, MACCE was more likely to occur in the HTX sub-group, which is shown graphically in Figure 2. Conclusion Interventional treatment of ACS in HTX patients is an option with a complication rate comparable to non-HTX patients and with a lower technical and procedural success - partly due to the diffuse nature of CAV and the involvement of distal and microvascular vessels. Overall MACCE and survival are inferior to the control population.Figure 1Figure 2

Endogen microvascular dysfunction is associated with worse outcomes in heart transplantation

Abstract Background Cardiac allograft vasculopathy (CAV) affects the health of both epicardial and microvascular blood vessels in heart transplants. Coronary microvascular dysfunction (CMD) has been associated with poor outcomes in the non-transplant population. Two patterns of microvascular dysfunction have been characterized, classical (low stress flow) and endogen (high rest flow). Whether these patterns of microvascular dysfunction are associated with outcomes in the transplant population has not been thoroughly evaluated. Purpose The purpose of the study was to assess the relationship between microvascular dysfunction and adverse outcomes in patients with heart transplants. Methods Patients with no history of angiographic CAV who underwent positron emission tomography myocardial perfusion imaging and were found to have normal perfusion (summed stress score = 0) were included in the study. Patients were then classified by microvascular dysfunction: normal (flow reserve ≥ 2.0) versus abnormal (flow reserve <2.0). Patients were further subclassified based on pattern of microvascular dysfunction, classical (stress myocardial flow <1.7 mL/min/g) and endogen (stress myocardial flow ≥1.7 mL/min/g). The two primary outcomes were all-cause mortality and a composite of death, heart failure hospitalization, acute coronary syndrome, and revascularization. Kaplan-Meier survival and Cox proportional regression were used to assess the relationship between microvascular function and outcomes. Results In total, 359 patients were enrolled in the study, of which 29 (8%) had classical CMD and 78 (22%) had endogen CMD. Patients with endogen CMD were more likely to be women (46%) compared to 31% for normal microvascular function and 24% for classical CMD. During a median follow up period of 2.0 years (Q1 1.7, Q3 2.3), 36 patients had an adverse event and 19 patients died. Endogen CMD was associated with a significantly higher risk of both the composite outcome, HR 2.30 (1.15 – 4.61), and all-cause mortality, 4.19 (1.64 – 10.73). Classical CMD was not associated with either the composite outcome, HR 0.88 (0.20 – 3.84) or death, HR 1.02 (0.12 – 8.33), however assessment of classical CMD was limited by small sample size. Conclusions Endogen-type CMD is associated with worse intermediate-term outcomes in transplant patients compared to normal microvascular function and classical-type CMD, although comparison to classical-type CMD was limited by small sample size.Table 1:DemographicsFigure 1:KM Survival Curves

ERBB4 activation prevents microvascular dysfunction in a large animal model of hypertensive heart disease

Abstract Background Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include ERBB4 stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure. Objectives To assess the effect NRG1/ERBB4 stimulation on CMD in hypertensive heart disease. Methods Hypertensive heart disease was induced in 12 Aachener minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 weeks and compared to 6 controls. The DOCA pigs were randomized to a weekly infusion of JK07, a NRG1 fusion protein with improved pharmacokinetic and pharmacodynamic properties, or vehicle. Microvascular resistance was measured using the bolus thermodilution method. Results DOCA significantly increased microvascular resistance compared to controls (from 14.5 to 19.9 mmHg.s, p = 0.028). This increase was abrogated by JK07 (11.3 mmHg.s, p = 0.018 vs DOCA). dP/dtmax increased by DOCA compared to controls (from 2415.5 to 4455.5 mmHg/s, p = 0.011), which was also abrogated by JK07 (3107.3 mmHg/s, p = 0.055 vs DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared to DOCA only (2.1 vs. 5.4 %, p = 0.026), but without difference in perivascular fibrosis (p = 0.48). JK07 did not affect myocyte cross-sectional area, capillary density, pericyte coverage, or microvascular vessel thickness. Conclusions ERBB4 activation by JK07 is capable to prevent CMD in a DOCA hypertensive pig model. Functional rather than structural alterations may explain the protective effects of JK07 on microvascular resistance.Visual summaryJK07 decreases microvascular resistance

Novel intravital approaches to quantify deep vascular structure and perfusion in the aging mouse brain using ultrasound localization microscopy (ULM)

Intra-vital visualization of deep cerebrovascular structures and blood flow in the aging brain has been a difficult challenge in the field of neurovascular research, especially when considering the key role played by the cerebrovasculature in the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). Traditional imaging methods face difficulties with the thicker skull of older brains, making high-resolution imaging and cerebral blood flow (CBF) assessment challenging. However, functional ultrasound (fUS) imaging, an emerging non-invasive technique, provides real-time CBF insights with notable spatial-temporal resolution. This study introduces an enhanced longitudinal fUS method for aging brains. Using elderly (24-month C57BL/6) mice, we detail replacing the skull with a polymethylpentene window for consistent fUS imaging over extended periods. Ultrasound localization mapping (ULM), involving the injection of a microbubble (<<10 μm) suspension allows for recording of high-resolution microvascular vessels and flows. ULM relies on the localization and tracking of single circulating microbubbles in the blood flow. A FIJI-based analysis interprets these high-quality ULM visuals. Testing on older mouse brains, our method successfully unveils intricate vascular specifics even in-depth, showcasing its utility for longitudinal studies that require ongoing evaluations of CBF and vascular aspects in aging-focused research.

Endoscopic characteristics and performance ofWASP classification in the diagnosis of colorectal sessile-serrated lesions in Vietnamese patients.

Sessile-serrated lesions (SSLs) are challenging to detect due to their typically subtle appearance. The Workgroup serrAted polypS and Polyposis (WASP) classification was developed to diagnose SSLs endoscopically. This study aimed to evaluate the endoscopic characteristics of SSLs and the performance of the WASP classification in the Vietnamese population. This cross-sectional study was carried out on patients with lower gastrointestinal symptoms who underwent colonoscopy at a Vietnamese tertiary hospital. Univariate and multivariate analyses were performed to identify endoscopic features associated with SSLs. The performance of the WASP classification for diagnosing SSLs was assessed, and SSLs were diagnosed according to the 2019 World Health Organization (WHO) criteria. There were 2489 patients, with a mean age of 52.1 ± 13.1 years and a female-to-male ratio of 1:1.1. A total of 121 specimens from 105 patients were diagnosed with SSLs. According to multivariate analysis, the endoscopic features significantly associated with SSLs were proximal location (odds ratio [OR]: 2.351; 95% confidence interval [CI]: 1.475-3.746), size >5 mm (OR: 2.447; 95% CI: 1.551-3.862), flat morphology (OR: 2.781; 95% CI: 1.533-5.044), irregular shape (OR: 4.516; 95% CI: 2.173-9.388), varicose microvascular vessels (OR: 5.030; 95% CI: 2.657-9.522), and dark spots inside the crypts (OR: 5.955; 95% CI: 3.291-10.776). The accuracy of the WASP classification for diagnosing SSLs was 94.0% (95% CI: 92.8%-95.0%). Proximal location, size >5 mm, flat morphology, irregular shape, varicose microvascular vessels, and dark spots inside the crypts were significantly associated with SSLs. The WASP classification had high accuracy in the diagnosis of SSLs.

Noninvasive assessment of human microvascular function in health and disease using incident dark-field microscopy.

Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.

Coronary Vascular Rarefaction in Heart Failure

Coronary vasculature rarefaction has been thought to play a role in the development of heart failure (HF), causing reduced myocardial perfusion; understanding the role that coronary rarefaction plays within HF presents an avenue for therapeutic strategies. We assessed the coronary microvascular and small vessel networks in left atrial appendage (LAA) samples to determine differences based on HF status. LAA samples were obtained from 15 consecutive patients during cardiac surgery (BMI: 22.8-37.9, age: 51-82, M:F: 9:6, NonHF:HF: 11:4). LAA samples were paraffn-embedded or flash frozen whereby 40 μm thick sections were then immunolabelled using DyLight 594 fluorescent tomato-lectin dye and z-stack images were rendered using microscopy. Z-stack images were input into Vesselucida360 and the vessel networks were three-dimensionally reconstructed via unbiased automatic tracing with multiple quantitative endpoints calculated. LAA samples were also used for proteomic analysis via LC-MS followed by statistical and pathway analyses to determine differences in protein expression and pertinent pathways as well as in a wide-scale gene expression array (NanoString) to further study underlying molecular targets. We found that the number of branching nodes and total vessel length in the coronary vascular network was decreased in HF compared to NonHF patients. Whereas the total volume and surface area were similar between HF and NonHF patients. Proteomic analysis and principal component analysis identified differences in protein profiles in the two groups, with pathway analysis identifying cardiac contraction and metabolism, along with hydrogen peroxide catabolic pathways downregulated in HF. Gene expression profiling identified numerous hypoxia response and oxidative stress response markers as downregulated in HF LAA samples. The data obtained show coronary vascular rarefaction occurring in HF patients, implying potential implications in the progression of HF. Additionally, proteomic data point to the downregulation of hydrogen peroxide response pathways as a potential mechanism for coronary microvascular rarefaction that we want to elucidate in future studies. T32 HL155011 (KAF) F31 NS132564 (KAF). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Enhanced Functional Ultrasound Imaging for Longitudinal Cerebrovascular Assessment in Aging Mouse Models

This study aims to enhance the visualization of deep cerebrovascular structures and blood flow in the aging brain, a key factor in understanding the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). We hypothesized that functional ultrasound (fUS) imaging through a polymethylpentene window could provide high-resolution insights into cerebral blood flow (CBF) in older mice. Employing this method, we replaced the skull of elderly (24-month-old C57BL/6) mice with a transparent window, allowing for consistent, non-invasive fUS imaging over time. We utilized ultrasound localization mapping (ULM) with a microbubble (approximately 10 micrometers (μm)) suspension for detailed mapping of microvascular vessels and flows. Data were analyzed using a FIJI-based platform to interpret high-quality ULM images. Our results demonstrate this novel method's effcacy in revealing intricate vascular details, proving its utility for longitudinal CBF assessments in physiological research in preclinical murine models and aging. This study was supported by the following funding sources: NIH R03AG070479, K01AG073614, R21AG080775, American Heart Association, Hevolution/AFAR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Predictive value of microcirculation for pediatric extracorporeal membrane oxygenation weaning test: Amonocentric prospective observational study.

Extracorporeal membrane oxygenation (ECMO) is widely used for children treated for refractory respiratory failures or refractory cardiogenic shock. Its duration depends on organ functions recovery. Weaning is decided using macro-circulatory tools, but microcirculation is not well evaluated. Sidestream dark-field video imaging is used to assess the perfusion of the sublingual microvascular vessels. The aim of this study was to assess the predictive value of microcirculatory indices in ECMO weaning. This prospective monocentric study examined pediatric patients at Trousseau Hospital between March 2017 and December 2020. The study included all patients from 35 weeks of gestational age to 18 years old who were treated with ECMO. Children were divided into two groups: one with stability after weaning and the other with instability after weaning. We collected clinical and biological data, ventilation parameters, extracorporeal membrane oxygenation parameters, and drugs used at admission and after the weaning test. Microcirculations videos were taken after weaning trials with echocardiography and blood gas monitoring. The study included 30 patients with a median age of 29 days (range: 1-770 days) at admission, including 18 patients who received venoarterial ECMO (60%). There were 19 children in the stability group and 11 in the instability group. Macrocirculatory and microcirculatory indices showed no differences between groups. The microvascular flow index was subnormal in both groups (2.3 (1.8-2.4) and 2.3 (2.3-2.6), respectively; p = 0.24). The microvascular indices were similar between cases of venovenous and venoarterial ECMO and between age groups. Microcirculation monitoring at the weaning phase did not predict the failure of ECMO weaning.

Sheet-based extrusion bioprinting: a new multi-material paradigm providing mid-extrusion micropatterning control for microvascular applications

As bioprinting advances into clinical relevance with patient-specific tissue and organ constructs, it must be capable of multi-material fabrication at high resolutions to accurately mimick the complex tissue structures found in the body. One of the most fundamental structures to regenerative medicine is microvasculature. Its continuous hierarchical branching vessel networks bridge surgically manipulatable arteries (∼1–6 mm) to capillary beds (∼10 µm). Microvascular perfusion must be established quickly for autologous, allogeneic, or tissue engineered grafts to survive implantation and heal in place. However, traditional syringe-based bioprinting techniques have struggled to produce perfusable constructs with hierarchical branching at the resolution of the arterioles (∼100-10 µm) found in microvascular tissues. This study introduces the novel CEVIC bioprinting device (i.e. Continuously Extruded Variable Internal Channeling), a multi-material technology that breaks the current extrusion-based bioprinting paradigm of pushing cell-laden hydrogels through a nozzle as filaments, instead, in the version explored here, extruding thin, wide cell-laden hydrogel sheets. The CEVIC device adapts the chaotic printing approach to control the width and number of microchannels within the construct as it is extruded (i.e. on-the-fly). Utilizing novel flow valve designs, this strategy can produce continuous gradients varying geometry and materials across the construct and hierarchical branching channels with average widths ranging from 621.5 ± 42.92% µm to 11.67 ± 14.99% µm, respectively, encompassing the resolution range of microvascular vessels. These constructs can also include fugitive/sacrificial ink that vacates to leave demonstrably perfusable channels. In a proof-of-concept experiment, a co-culture of two microvascular cell types, endothelial cells and pericytes, sustained over 90% viability throughout 1 week in microchannels within CEVIC-produced gelatin methacryloyl-sodium alginate hydrogel constructs. These results justify further exploration of generating CEVIC-bioprinted microvasculature, such as pre-culturing and implantation studies.

Influence of excessive salt consumption on the functional state of microvascular vessels of the skin of rats with renal dysfunction

Background. Cardiovascular complications are common in chronic kidney disease (CKD). The relationship between the cardiovascular system and the kidneys is complex and diverse, but the question of the mechanisms of the influence of excess NaCl consumption on the functional state of blood vessels during renal dysfunction remains relevant.The aim: to evaluate the effect of a high-salt diet on the functional state of microcirculatory vessels (MCR) of the skin in rats at an early stage of renal dysfunction.Material and Methods. The study was conducted on Wistar rats. The first SO group included animals subjected to sham surgery (SO) and receiving a standard diet (0.34% NaCl); in the second, HS group – animals that also underwent a sham operation, but received a high-salt diet (4% NaCl); in the third, NE group – rats subjected to ¾ nephrectomy (NE) and receiving a standard diet; the fourth, HS+ NE group included rats subjected to ¾ NE and fed a high-salt diet (4% NaCl). Blood pressure (BP) was measured in the tail using the cuff method (Sistola, Russia), MCR was assessed using laser Doppler flowmetry (LDF). The reactivity of skin microvessels was assessed by changes in the MCR index before and after iontophoresis of acetylcholine (ACh) and sodium nitroprusside (NP). Based on the assessment of the spectral characteristics of fluctuations in the MCR index obtained using Wavelet analysis, the value of endothelial, neurogenic and myogenic microvascular tone was calculated.Results. 4 months after ¾ NE, rats showed a decrease in the excretory function of the kidneys. In rats on a highsalt diet, an increase in blood urea levels was noted. The blood pressure in rats of the SO+HS group did not significantly differ from the control animals of the SO group (131 ± 8 and 125 ± 4 mmHg, respectively, NS), NE led to a significant increase in blood pressure (135 ± 5 mmHg in rats of the NE group, and 145 ± 7 mmHg – in the NE+HS group). The average MCR was higher in rats receiving a high-salt diet (SO+HS and NE+HS groups), compared with animals of the corresponding group receiving a standard diet. The combination of NE and high-salt load has an inhibitory effect on the amplitude of fluctuations in the intensity of perfusion in all studied ranges: endothelial, neurogenic and myogenic, while the calculated value of skin microvascular tone in three ranges was the highest in NE+HS group rats. In all experimental groups, the reactivity to AH was reduced compared with the SO group, and after NP iontophoresis, the average perfusion rate significantly decreased only in groups of animals receiving a high-salt diet: SO+HS and NE+HS.Conclusion. A high-salt diet in rats with an initial stage of renal dysfunction contributes to an increase in blood pressure and a decrease in natriuresis compared with animals with NE who received a standard diet. With excessive consumption of table salt in rats after NE, the intensity of cutaneous MCR increases, while reducing the variability of the MCR index. A high-salt diet in rats with NE modifies the characteristics of the spectral components of fluctuations in the MCR index, indicating an increase in tonic effects on skin microvessels in the endothelial, neurogenic and myogenic ranges. With hypernatrial load, animals with ¾ NE have a decrease in the reactivity of cutaneous microvessels to AH and NP, which is mediated by both a decrease in endothelial NO production and a decrease in MMC sensitivity to NO.

Quantitative microvascular analysis in different stages of retinitis pigmentosa using optical coherence tomography angiography

As retinitis pigmentosa (RP) is chronic and progressive, the chronological sequence of microvascular changes is important for understanding its pathophysiology. We aimed to investigate retinal and choroidal microvascular changes according to the RP stages. The stages of RP were classified into three stages according to the integrity and width of the inner segment ellipsoid zone: early, ≥ 2500 μm; moderate, < 2500 μm; advanced, absence. Using optical coherence tomography angiography, quantitative microvascular parameters were analyzed. In total, 91 eyes from 49 patients were included. For the superficial capillary plexus (SCP) and deep capillary plexus (DCP), perfusion densities (PDs) in the early stage (SCP: 37.32 ± 8.11%; DCP: 21.19 ± 9.15%) were greater than those in moderate (SCP: 34.16 ± 6.65%, P = 0.011; DCP: 15.67 ± 8.85%, P = 0.031) and advanced stages (SCP: 33.71 ± 9.02%, P = 0.030; DCP: 12.83 ± 6.29%, P < 0.001). The choroidal vascularity index in the early stage (0.58 ± 0.03) was greater than those in the moderate (0.57 ± 0.02, P = 0.017) and advanced stage (0.56 ± 0.02, P = 0.033). The area and perimeter of foveal avascular zone (FAZ) in advanced stage (0.44 ± 0.26 mm2, 2.96 ± 0.86 mm, respectively) were larger than those in early (0.26 ± 0.11 mm2, P = 0.020; 2.19 ± 0.53 mm, P = 0.006, respectively) and moderate stage (0.28 ± 0.13 mm2, P = 0.043; 2.24 ± 0.67 mm, P = 0.013, respectively). During RP disease progression, retinal and choroidal microvascular vessel density decreases in the early stage, followed by FAZ enlargement in the advanced stage.

Obstructive sleep apnea, nocturnal hypoxemia, and retinal microvasculature: The Atherosclerosis Risk in Communities Study.

Retinal microvascular pathology (RMP) and obstructive sleep apnea (OSA) are both cardiovascular disease risk factors. Limited data exists on their interrelationship. We tested the hypotheses that OSA and nocturnal hypoxemia would be associated with RMP and vessel calibers. We conducted a quasi-cross-sectional analysis of 1625 participants in the Atherosclerosis Risk in Communities Sleep Heart Health Study. Participants completed in-home polysomnography monitoring (1996-1998) and were categorized by OSA severity (apnea-hypopnea index: <5, 5-14.9, and ≥15) and proportion of total sleep time with oxygen saturation < 90% (T90). Retinal photography (1993-1995) was used to assess RMP and measure vascular diameters (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]). Logistic and linear models were adjusted for demographics, behaviors, and BMI. Of the participants, 19% had OSA (AHI > 15) and 4% had RMP. Severe OSA was not associated with RMP [OR (95% CI): 1.08 (0.49 to 2.38)] or CRAE in adjusted models. OSA severity showed a positive linear relationship with CRVE; adjusted mean CRVE for those with OSA was 195.8 μm compared to 193.2 μm for those without OSA (Ptrend = 0.03). T90 was strongly associated with CRVE, but not with RMP or CRAE. Adjusted mean CRVE for T90 ≥ 5% was 199.0 and 192.9 for T90 < 1% (ptrend < 0.0001). OSA and T90 were not associated with RMP or CRAE. However, both OSA and T90 ≥ 5% were associated with wider venules, which may be early and indicative changes of increased inflammation and future risk of stroke and CHD.

Thrombopoietin mimetic therapy alleviates radiation-induced bone marrow vascular injury in a bone marrow transplant mouse model.

There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs. To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT. TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (Ktrans) of contrast within the BM vascular niche, as well as the fractional volume (vec ) of extracellular extravascular tissue (EES). No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, Ktrans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement in mice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery.

Scalable and stable human pluripotent stem cell-derived microvascular-like endothelial cells for cardiac regeneration and disease modelling applications

Abstract Introduction The microvasculature is a vital constituent of the adult human vasculature 1. Cardiac tissue engineering, in vitro models of cardiac remodelling and regeneration, and disease models of the microvasculature would benefit from the inclusion of well-characterised, phenotypically stable microvascular-like endothelial cells (ECs) that could be generated at scale without xenogeneic reagents. Primary microvascular ECs have been utilised for such applications however, they are susceptible to passaging-induced senescence². Moreover, alternative solutions including current protocols for the derivation of human pluripotent stem cell-derived ECs (hPSC-ECs) generate cells with a heterogenous vascular identity that often transdifferentiate into non-EC lineages³. Purpose The purpose of this study was to create a 3D, xenogeneic-free differentiation protocol that yielded stable hPSC-derived microvascular-like ECs (hPSC-MVECs) at scale. Methods Endothelial differentiation of hPSCs was conducted in 2D adherent monolayers and within stirred 3D bioreactors for 12 days. Thereafter, CD31pos ECs were isolated via fluorescence-activated cell sorting (FACS) and cultured for a further 14 days. Gene expression analysis of hPSCs undergoing 2D and 3D differentiation was evaluated via RT-qPCR. The day 26 hPSC-ECs were treated with VEGFA (0 – 50 ng/ml) for a further 7 days and evaluated for CD31 expression via high-content image analysis. The angiogenic profiles of 2D-, 3D-, and 3D-hPSC-ECs cultured in high concentration VEGFA (herein, 3D+V), relative to primary Human Cardiac Microvascular Endothelial Cells (HMVEC-Cs) was assessed using the Proteome Profiler Human Angiogenesis Array. Transcriptomic analysis of these EC populations was subsequently conducted via single-cell RNA sequencing (scRNA-seq). Results Complex vascular clusters emerged by day 12 of the 3D differentiation protocol (fig. 1). The emergent 3D hPSC-ECs had a comparable expression of PECAM1 and CDH5 relative to 2D-derived hPSC-ECs however, VEGFA expression was significantly reduced (P&amp;lt;0.01, fig. 2A). VEGFA treatment at 50 ng/ml yielded phenotypically stable hPSC-ECs (3D+V, fig. 2B). Principal component analysis of the angiogenic factors assayed for revealed 3D+V hPSC-ECs clustered with HMVEC-Cs (fig. 2C). scRNA-seq identified a subset of 3D-derived hPSC-ECs expressing genes associated with microvascular vessels (GMFG, PLVAP), capillary ECs (RGCC, GLUL), and angiogenic tip cells (ESM1, HSPG2). Conclusion The scalable and xenogeneic-free 3D protocol outlined within allows for the attainment of hPSC-derived microvascular-like ECs with high angiogenic potential. The absence of Matrigel enhances the translational capacity of the hPSC-MVECs arising from this protocol that could now be derived from patient-specific hPSC lines for evaluation in pre-clinical models of post-myocardial infarction cardiac regeneration or for in vivo models of cardiac remodelling and microvasculature disease.

Magnetic Resonance Deep Learning Radiomic Model Based on Distinct Metastatic Vascular Patterns for Evaluating Recurrence-Free Survival in Hepatocellular Carcinoma.

The metastatic vascular patterns of hepatocellular carcinoma (HCC) are mainly microvascular invasion (MVI) and vessels encapsulating tumor clusters (VETC). However, most existing VETC-related radiological studies still focus on the prediction of VETC status. This study aimed to build and compare VETC-MVI related models (clinical, radiomics, and deep learning) associated with recurrence-free survival of HCC patients. Retrospective. 398 HCC patients (349 male, 49 female; median age 51.7 years, and age range: 22-80 years) who underwent resection from five hospitals in China. The patients were randomly divided into training cohort (n = 358) and test cohort (n = 40). 3-T, pre-contrast T1-weighted imaging spoiled gradient recalled echo (T1WI SPGR), T2-weighted imaging fast spin echo (T2WI FSE), and contrast enhanced arterial phase (AP), delay phase (DP). Two radiologists performed the segmentation of HCC on T1WI, T2WI, AP, and DP images, from which radiomic features were extracted. The RFS related clinical characteristics (VETC, MVI, Barcelona stage, tumor maximum diameter, and alpha fetoprotein) and radiomic features were used to build the clinical model, clinical-radiomic (CR) nomogram, deep learning model. The follow-up process was done 1 month after resection, and every 3 months subsequently. The RFS was defined as the date of resection to the date of recurrence confirmed by radiology or the last follow-up. Patients were followed up until December 31, 2022. Univariate COX regression, least absolute shrinkage and selection operator (LASSO), Kaplan-Meier curves, log-rank test, C-index, and area under the curve (AUC). P < 0.05 was considered statistically significant. The C-index of deep learning model achieved 0.830 in test cohort compared with CR nomogram (0.731), radiomic signature (0.707), and clinical model (0.702). The average RFS of the overall patients was 26.77 months (range 1-80 months). MR deep learning model based on VETC and MVI provides a potential tool for survival assessment. 3 TECHNICAL EFFICACY: Stage 3.

Laparoscopic ischemic conditioning of the stomach prior to esophagectomy induces gastric neo-angiogenesis

BackgroundThe risk of an anastomotic leakage (AL) following Ivor-Lewis esophagectomy is increased in patients with calcifications of the aorta or a stenosis of the celiac trunc. Ischemic conditioning (ISCON) of the gastric conduit prior to esophagectomy is supposed to improve gastric vascularization at the anastomotic site. The prospective ISCON trial was conducted to proof the safety and feasibility of this strategy with partial gastric devascularization 14 days before esophagectomy in esophageal cancer patients with a compromised vascular status. This work reports the results from a translational project of the ISCON trial aimed to investigate variables of neo-angiogenesis. MethodsTwenty esophageal cancer patients scheduled for esophagectomy were included in the ISCON trial. Serum samples (n = 11) were collected for measurement of biomarkers and biopsies (n = 12) of the gastric fundus were taken before and after ISCON of the gastric conduit. Serum samples were analyzed including 62 different cytokines. Vascularization of the gastric mucosa was assessed on paraffin-embedded sections stained against CD34 to detect the degree of microvascular density and vessel size. ResultsBetween November 2019 and January 2022 patients were included in the ISCON Trial. While serum samples showed no differences regarding cytokine levels before and after ISCON biopsies of the gastric mucosa demonstrated a significant increase in microvascular density after ISCON as compared to the corresponding gastric sample before the intervention. ConclusionThe data prove that ISCON of the gastric conduit as esophageal substitute induces significant neo-angiogenesis in the gastric fundus which is considered as surrogate of an improved vascularization at the anastomotic site.

The Role of Shear Stress in Coronary Artery Disease.

Coronary artery disease is the leading cause of morbidity and mortality worldwide, especially in developed countries, with an increasing incidence in developing countries. Despite the advances in cardiology, there are yet many unanswered questions about the natural history of coronary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, "vulnerable" plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident disease. Recent findings have indicated that apart from cardiovascular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as endothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary artery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunction of epicardial and microvascular vessels, inflammation, and their complex associations, underlying in parallel the clinical perspectives of these findings.