Essential hypertension (HT) is the global health problem and is a major risk factor for the development of cardiovascular and kidney disease. High salt intake has been associated with HT and impaired kidney sodium excretion is considered to be a major mechanism for the development of HT. Although kidney has a very important role in regulation of BP, this traditional view of BP regulation was challenged by recent findings suggesting that nonosmotic tissue sodium deposition is very important for BP regulation. This new paradigm indicates that sodium can be stored and deposited nonosmotically in the interstitium without water retention and without increased BP. One of the major determinants of this deposition is glycosaminoglycans (GAGs). By binding to GAGs found in the endothelial surface layer (ESL) which contains glycocalyx, sodium is osmotically inactivated and not induce concurrent water retention. Thus, GAGs has important function for homeostatic BP and sodium regulation. In the current review, we summarized the role of GAGs in ESL and BP regulation.
{"title":"The role of glycosaminoglycans in blood pressure regulation","authors":"Baris Afsar, Rengin Elsurer Afsar","doi":"10.1111/micc.12832","DOIUrl":"10.1111/micc.12832","url":null,"abstract":"<p>Essential hypertension (HT) is the global health problem and is a major risk factor for the development of cardiovascular and kidney disease. High salt intake has been associated with HT and impaired kidney sodium excretion is considered to be a major mechanism for the development of HT. Although kidney has a very important role in regulation of BP, this traditional view of BP regulation was challenged by recent findings suggesting that nonosmotic tissue sodium deposition is very important for BP regulation. This new paradigm indicates that sodium can be stored and deposited nonosmotically in the interstitium without water retention and without increased BP. One of the major determinants of this deposition is glycosaminoglycans (GAGs). By binding to GAGs found in the endothelial surface layer (ESL) which contains glycocalyx, sodium is osmotically inactivated and not induce concurrent water retention. Thus, GAGs has important function for homeostatic BP and sodium regulation. In the current review, we summarized the role of GAGs in ESL and BP regulation.</p>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 8","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41139652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caitlin R. Francis, Makenzie L. Bell, Marina M. Skripnichuk, Erich J. Kushner
Objective
Endocytosis is a process vital to angiogenesis and vascular homeostasis. In pathologies where supraphysiological growth factor signaling underlies disease etiology, such as in diabetic retinopathy and solid tumors, strategies to limit chronic growth factor signaling by way of blunting endocytic processes have been shown to have tremendous clinical value. ADP ribosylation factor 6 (Arf6) is a small GTPase that promotes the assembly of actin necessary for clathrin-mediated and clathrin-independent endocytosis. In its absence, growth factor signaling is greatly diminished, which has been shown to ameliorate pathological signaling input in diseased vasculature. However, it is less clear if there are bystander effects related to loss of Arf6 on angiogenic behaviors. Our goal was to provide an analysis of Arf6's function in angiogenic endothelium, focusing on its role in actin and endocytosis as well as sprouting morphogenesis.
Methods
Primary endothelial cells were cultured in both 2D and 3D environments. Here, endothelial cells were fixed and stained for various proteins or transfected with fluorescently-tagged constructs for live-cell imaging.
Results
We found that Arf6 localized to both filamentous actin and sites of endocytosis in two-dimensional culture. Loss of Arf6 distorted both apicobasal polarity and reduced the total cellular filamentous actin content, which may be the primary driver underlying gross sprouting dysmorphogenesis in its absence.
Conclusions
Our findings highlight that endothelial Arf6 is a potent mediator of both actin regulation and endocytosis and is required for proper sprout formation.
{"title":"Arf6 is required for endocytosis and filamentous actin assembly during angiogenesis in vitro","authors":"Caitlin R. Francis, Makenzie L. Bell, Marina M. Skripnichuk, Erich J. Kushner","doi":"10.1111/micc.12831","DOIUrl":"10.1111/micc.12831","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Endocytosis is a process vital to angiogenesis and vascular homeostasis. In pathologies where supraphysiological growth factor signaling underlies disease etiology, such as in diabetic retinopathy and solid tumors, strategies to limit chronic growth factor signaling by way of blunting endocytic processes have been shown to have tremendous clinical value. ADP ribosylation factor 6 (Arf6) is a small GTPase that promotes the assembly of actin necessary for clathrin-mediated and clathrin-independent endocytosis. In its absence, growth factor signaling is greatly diminished, which has been shown to ameliorate pathological signaling input in diseased vasculature. However, it is less clear if there are bystander effects related to loss of Arf6 on angiogenic behaviors. Our goal was to provide an analysis of Arf6's function in angiogenic endothelium, focusing on its role in actin and endocytosis as well as sprouting morphogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Primary endothelial cells were cultured in both 2D and 3D environments. Here, endothelial cells were fixed and stained for various proteins or transfected with fluorescently-tagged constructs for live-cell imaging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that Arf6 localized to both filamentous actin and sites of endocytosis in two-dimensional culture. Loss of Arf6 distorted both apicobasal polarity and reduced the total cellular filamentous actin content, which may be the primary driver underlying gross sprouting dysmorphogenesis in its absence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings highlight that endothelial Arf6 is a potent mediator of both actin regulation and endocytosis and is required for proper sprout formation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 8","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nien-Wen Hu, Banks M. Lomel, Elijah W. Rice, Mir Md Nasim Hossain, Malisa Sarntinoranont, Timothy W. Secomb, Walter L. Murfee, Peter Balogh
Objective
Fluid shear stress is thought to be a regulator of endothelial cell behavior during angiogenesis. The link, however, requires an understanding of stress values at the capillary level in angiogenic microvascular networks. Critical questions remain. What are the stresses? Do capillaries experience similar stress magnitudes? Can variations explain vessel-specific behavior? The objective of this study was to estimate segment-specific shear stresses in angiogenic networks.
Methods
Images of angiogenic networks characterized by increased vascular density were obtained from rat mesenteric tissues stimulated by compound 48/80-induced mast cell degranulation. Vessels were identified by perfusion of a 40 kDa fixable dextran prior to harvesting and immunolabeling for PECAM. Using a network flow-based segment model with physiologically relevant parameters, stresses were computed per vessel for regions across multiple networks.
Results
Stresses ranged from 0.003 to 2328.1 dyne/cm2 and varied dramatically at the capillary level. For all regions, the maximum segmental shear stresses were for capillary segments. Stresses along proximal capillaries branching from arteriole inlets were increased compared to stresses along capillaries in more distal regions.
Conclusions
The results highlight the variability of shear stresses along angiogenic capillaries and motivate new discussions on how endothelial cells may respond in vivo to segment-specific microenvironment during angiogenesis.
{"title":"Estimation of shear stress heterogeneity along capillary segments in angiogenic rat mesenteric microvascular networks","authors":"Nien-Wen Hu, Banks M. Lomel, Elijah W. Rice, Mir Md Nasim Hossain, Malisa Sarntinoranont, Timothy W. Secomb, Walter L. Murfee, Peter Balogh","doi":"10.1111/micc.12830","DOIUrl":"10.1111/micc.12830","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Fluid shear stress is thought to be a regulator of endothelial cell behavior during angiogenesis. The link, however, requires an understanding of stress values at the capillary level in angiogenic microvascular networks. Critical questions remain. What are the stresses? Do capillaries experience similar stress magnitudes? Can variations explain vessel-specific behavior? The objective of this study was to estimate segment-specific shear stresses in angiogenic networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Images of angiogenic networks characterized by increased vascular density were obtained from rat mesenteric tissues stimulated by compound 48/80-induced mast cell degranulation. Vessels were identified by perfusion of a 40 kDa fixable dextran prior to harvesting and immunolabeling for PECAM. Using a network flow-based segment model with physiologically relevant parameters, stresses were computed per vessel for regions across multiple networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Stresses ranged from 0.003 to 2328.1 dyne/cm<sup>2</sup> and varied dramatically at the capillary level. For all regions, the maximum segmental shear stresses were for capillary segments. Stresses along proximal capillaries branching from arteriole inlets were increased compared to stresses along capillaries in more distal regions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results highlight the variability of shear stresses along angiogenic capillaries and motivate new discussions on how endothelial cells may respond in vivo to segment-specific microenvironment during angiogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 8","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10246233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jaime Fernández-Sarmiento, Ricardo Hernández-Sarmiento, María Paula Salazar, Sofia Barrera, Valeria Castilla, Catalina Duque
Objective
The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes of interest.
Methods
Observational, prospective study in children with sepsis. The primary outcome was the association between hypoalbuminemia and microcirculation disorders, endothelial activation and glycocalyx degradation using a perfused boundary region (PBR) (abnormal >2.0 μm on sublingual video microscopy) or plasma biomarkers (syndecan-1, angiopoietin-2).
Results
A total of 125 patients with sepsis were included. The median age was 2.0 years (IQR 0.5–12.5). Children with hypoalbuminemia had more abnormal microcirculation with a higher PBR (2.16 μm [IQR 2.03–2.47] vs. 1.92 [1.76–2.28]; p = .01) and more 4–6 μm capillaries recruited (60% vs. 40%; p = .04). The low albumin group that had the worst PBR had the most 4–6 μm capillaries recruited (rho 0.29; p < .01), 48% higher Ang-2 (p = .04), worse annexin A5 (p = 0.03) and no syndecan-1 abnormalities (p = .21). Children with hypoalbuminemia and a greater percentage of blood volume in their capillaries needed mechanical ventilation more often (56.3% vs. 43.7%; aOR 2.01 95% CI 1.38–3.10: p < .01).
Conclusions
In children with sepsis, an association was found between hypoalbuminemia and microcirculation changes, vascular permeability, and greater endothelial glycocalyx degradation.
{"title":"The association between hypoalbuminemia and microcirculation, endothelium, and glycocalyx disorders in children with sepsis","authors":"Jaime Fernández-Sarmiento, Ricardo Hernández-Sarmiento, María Paula Salazar, Sofia Barrera, Valeria Castilla, Catalina Duque","doi":"10.1111/micc.12829","DOIUrl":"10.1111/micc.12829","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes of interest.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Observational, prospective study in children with sepsis. The primary outcome was the association between hypoalbuminemia and microcirculation disorders, endothelial activation and glycocalyx degradation using a perfused boundary region (PBR) (abnormal >2.0 μm on sublingual video microscopy) or plasma biomarkers (syndecan-1, angiopoietin-2).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 125 patients with sepsis were included. The median age was 2.0 years (IQR 0.5–12.5). Children with hypoalbuminemia had more abnormal microcirculation with a higher PBR (2.16 μm [IQR 2.03–2.47] vs. 1.92 [1.76–2.28]; <i>p</i> = .01) and more 4–6 μm capillaries recruited (60% vs. 40%; <i>p</i> = .04). The low albumin group that had the worst PBR had the most 4–6 μm capillaries recruited (rho 0.29; <i>p</i> < .01), 48% higher Ang-2 (<i>p</i> = .04), worse annexin A5 (<i>p</i> = 0.03) and no syndecan-1 abnormalities (<i>p</i> = .21). Children with hypoalbuminemia and a greater percentage of blood volume in their capillaries needed mechanical ventilation more often (56.3% vs. 43.7%; aOR 2.01 95% CI 1.38–3.10: <i>p</i> < .01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In children with sepsis, an association was found between hypoalbuminemia and microcirculation changes, vascular permeability, and greater endothelial glycocalyx degradation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 8","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10101798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evan H. Phillips, Vytautas P. Bindokas, Dahee Jung, Jay Teamer, Jan K. Kitajewski, R. John Solaro, Beata M. Wolska, Steve Seung-Young Lee
Objective
Three-dimensional (3D) microscopy and image data analysis are necessary for studying the morphology of cardiac lymphatic vessels (LyVs) and their association with other cell types. We aimed to develop a methodology for 3D multiplexed lightsheet microscopy and highly sensitive and quantitative image analysis to identify pathological remodeling in the 3D morphology of LyVs in young adult mouse hearts with familial hypertrophic cardiomyopathy (HCM).
Methods
We developed a 3D lightsheet microscopy workflow providing a quick turn-around (as few as 5–6 days), multiplex fluorescence detection, and preservation of LyV structure and epitope markers. Hearts from non-transgenic and transgenic (TG) HCM mice were arrested in diastole, retrograde perfused, immunolabeled, optically cleared, and imaged. We built an image-processing pipeline to quantify LyV morphological parameters at the chamber and branch levels.
Results
Chamber-specific pathological alterations of LyVs were identified, and significant changes were seen in the right atrium (RA). TG hearts had a higher volume percent of ER-TR7+ fibroblasts and reticular fibers. In the RA, we found associations between ER-TR7+ volume percent and both LyV segment density and median diameter.
Conclusions
This workflow and study enabled multi-scale analysis of pathological changes in cardiac LyVs of young adult mice, inviting ideas for research on LyVs in cardiac disease.
{"title":"Three-dimensional spatial quantitative analysis of cardiac lymphatics in the mouse heart","authors":"Evan H. Phillips, Vytautas P. Bindokas, Dahee Jung, Jay Teamer, Jan K. Kitajewski, R. John Solaro, Beata M. Wolska, Steve Seung-Young Lee","doi":"10.1111/micc.12826","DOIUrl":"10.1111/micc.12826","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Three-dimensional (3D) microscopy and image data analysis are necessary for studying the morphology of cardiac lymphatic vessels (LyVs) and their association with other cell types. We aimed to develop a methodology for 3D multiplexed lightsheet microscopy and highly sensitive and quantitative image analysis to identify pathological remodeling in the 3D morphology of LyVs in young adult mouse hearts with familial hypertrophic cardiomyopathy (HCM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We developed a 3D lightsheet microscopy workflow providing a quick turn-around (as few as 5–6 days), multiplex fluorescence detection, and preservation of LyV structure and epitope markers. Hearts from non-transgenic and transgenic (TG) HCM mice were arrested in diastole, retrograde perfused, immunolabeled, optically cleared, and imaged. We built an image-processing pipeline to quantify LyV morphological parameters at the chamber and branch levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Chamber-specific pathological alterations of LyVs were identified, and significant changes were seen in the right atrium (RA). TG hearts had a higher volume percent of ER-TR7<sup>+</sup> fibroblasts and reticular fibers. In the RA, we found associations between ER-TR7<sup>+</sup> volume percent and both LyV segment density and median diameter.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This workflow and study enabled multi-scale analysis of pathological changes in cardiac LyVs of young adult mice, inviting ideas for research on LyVs in cardiac disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 7","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12826","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10498220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Coronary microvascular dysfunction is a high-risk factor for many cardiovascular events. However, because of multiple risk factors and limited understanding about its underlying pathophysiological mechanisms, it was easily misdiagnosed. Therefore, its clinical diagnosis and treatment were greatly restricted. Coronary microcirculation refers to microvessels that play an important role in the physiological regulation of myocardial perfusion and regulating blood flow distribution, fulfilling myocardial metabolic needs and moderating peripheral vascular resistance. In coronary microvascular dysfunction, vascular endothelial celldamage is a critical link. The main feature of early coronary microvascular dysfunction is the impairment of endothelial cell proliferation, adhesion, migration, apoptosis, and secretion. Moreover, coronary microvascular dysfunction risk factors include hyperglycemia, lipid metabolism disorders, ischemia-reperfusion injury, aging, and hypertension, similar to coronary atherosclerosis. There are various mechanisms by which these risk factors harm endothelial function and cause microcirculatory disturbances. Therefore, we reviewed coronary microvascular dysfunction's risk factors and pathogenesis in this article.
{"title":"Progress in molecular mechanisms of coronary microvascular dysfunction","authors":"Hao Li, Yuping Gao, Yuanyuan Lin","doi":"10.1111/micc.12827","DOIUrl":"10.1111/micc.12827","url":null,"abstract":"<p>Coronary microvascular dysfunction is a high-risk factor for many cardiovascular events. However, because of multiple risk factors and limited understanding about its underlying pathophysiological mechanisms, it was easily misdiagnosed. Therefore, its clinical diagnosis and treatment were greatly restricted. Coronary microcirculation refers to microvessels that play an important role in the physiological regulation of myocardial perfusion and regulating blood flow distribution, fulfilling myocardial metabolic needs and moderating peripheral vascular resistance. In coronary microvascular dysfunction, vascular endothelial celldamage is a critical link. The main feature of early coronary microvascular dysfunction is the impairment of endothelial cell proliferation, adhesion, migration, apoptosis, and secretion. Moreover, coronary microvascular dysfunction risk factors include hyperglycemia, lipid metabolism disorders, ischemia-reperfusion injury, aging, and hypertension, similar to coronary atherosclerosis. There are various mechanisms by which these risk factors harm endothelial function and cause microcirculatory disturbances. Therefore, we reviewed coronary microvascular dysfunction's risk factors and pathogenesis in this article.</p>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 7","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10052215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joana Costa d'Avila, Aluana Santana Carlos, Raimundo Lima Vieira, Carla Vergueiro, Aline Teixeira Lima, Isaias dos Santos Silva, Vivian Carvalho de Figueiredo, Paulo Henrique Petrone Chateaubriand, Adalgiza Mafra Moreno, Hugo Caire de Castro Faria Neto, Vanessa Estato, Rodrigo Azeredo Siqueira
Objectives
This study aimed to evaluate the effects of the antidiabetics liraglutide, a GLP-1 analog, and empagliflozin, an SGLT-2 inhibitor, on the brain microcirculation of diabetic rats.
Methods
Type 2 diabetes mellitus (DM) was experimentally induced in male Wistar rats by combining a high-fat diet and a low dose of streptozotocin (35 mg/kg). Liraglutide (100 μg/kg s.c.) and empagliflozin (10 mg/kg, oral) were administered for 5 weeks. Body weight was monitored periodically. Oral glucose tolerance, fasting glycemia, and blood triglycerides were evaluated after the treatments. Endothelial–leukocyte interactions in the brain microcirculation and structural capillary density were assessed.
Results
DM rats presented metabolic and cerebrovascular alterations. Liraglutide treatment decreased body weight and blood triglycerides of DM rats. Empagliflozin treatment improved glucose tolerance but only the combination therapy significantly reduced fasting blood glucose. Both treatments and their combination reduced leukocyte adhesion into the endothelium of brain venules. However, empagliflozin was more effective in preventing DM-induced microvascular rarefaction.
Conclusion
These findings suggest that chronic treatment with SGLT2 inhibitors and GLP-1 receptor agonists may serve as potential therapeutic approaches to prevent microvascular complications associated with diabetes.
{"title":"Beneficial effects of empagliflozin and liraglutide on the cerebral microcirculation of diabetic rats","authors":"Joana Costa d'Avila, Aluana Santana Carlos, Raimundo Lima Vieira, Carla Vergueiro, Aline Teixeira Lima, Isaias dos Santos Silva, Vivian Carvalho de Figueiredo, Paulo Henrique Petrone Chateaubriand, Adalgiza Mafra Moreno, Hugo Caire de Castro Faria Neto, Vanessa Estato, Rodrigo Azeredo Siqueira","doi":"10.1111/micc.12825","DOIUrl":"10.1111/micc.12825","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to evaluate the effects of the antidiabetics liraglutide, a GLP-1 analog, and empagliflozin, an SGLT-2 inhibitor, on the brain microcirculation of diabetic rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Type 2 diabetes mellitus (DM) was experimentally induced in male Wistar rats by combining a high-fat diet and a low dose of streptozotocin (35 mg/kg). Liraglutide (100 μg/kg s.c.) and empagliflozin (10 mg/kg, oral) were administered for 5 weeks. Body weight was monitored periodically. Oral glucose tolerance, fasting glycemia, and blood triglycerides were evaluated after the treatments. Endothelial–leukocyte interactions in the brain microcirculation and structural capillary density were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DM rats presented metabolic and cerebrovascular alterations. Liraglutide treatment decreased body weight and blood triglycerides of DM rats. Empagliflozin treatment improved glucose tolerance but only the combination therapy significantly reduced fasting blood glucose. Both treatments and their combination reduced leukocyte adhesion into the endothelium of brain venules. However, empagliflozin was more effective in preventing DM-induced microvascular rarefaction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that chronic treatment with SGLT2 inhibitors and GLP-1 receptor agonists may serve as potential therapeutic approaches to prevent microvascular complications associated with diabetes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 7","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12825","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9953870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ZheHao Tan, Pam Hall, Adam Costin, Simon A. Crawford, Georg Ramm, Connie H. Y. Wong, A. Richard Kitching, Michael J. Hickey
Objective
The endothelial surface layer (ESL), a layer of macromolecules on the surface of endothelial cells, can both impede and facilitate leukocyte recruitment. However, its role in monocyte and neutrophil recruitment in glomerular capillaries is unknown.
Methods
We used multiphoton intravital microscopy to examine monocyte and neutrophil behavior in the glomerulus following ESL disruption with hyaluronidase.
Results
Constitutive retention and migration of monocytes and neutrophils within the glomerular microvasculature was unaltered by hyaluronidase. Consistent with this, inhibition of the hyaluronan-binding molecule CD44 also failed to modulate glomerular trafficking of these immune cells. To investigate the contribution of the ESL during acute inflammation, we induced glomerulonephritis via in situ immune complex deposition. This resulted in increases in glomerular retention of monocytes and neutrophils but did not induce marked reduction in the glomerular ESL. Furthermore, hyaluronidase treatment did not modify the prolonged retention of monocytes and neutrophils in the acutely inflamed glomerular microvasculature.
Conclusions
These observations indicate that, despite evidence that the ESL has the capacity to inhibit leukocyte-endothelial cell interactions while also containing adhesive ligands for immune cells, neither of these functions modulate trafficking of monocytes and neutrophils in steady-state or acutely-inflamed glomeruli.
{"title":"Removal of the endothelial surface layer via hyaluronidase does not modulate monocyte and neutrophil interactions with the glomerular endothelium","authors":"ZheHao Tan, Pam Hall, Adam Costin, Simon A. Crawford, Georg Ramm, Connie H. Y. Wong, A. Richard Kitching, Michael J. Hickey","doi":"10.1111/micc.12823","DOIUrl":"10.1111/micc.12823","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The endothelial surface layer (ESL), a layer of macromolecules on the surface of endothelial cells, can both impede and facilitate leukocyte recruitment. However, its role in monocyte and neutrophil recruitment in glomerular capillaries is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used multiphoton intravital microscopy to examine monocyte and neutrophil behavior in the glomerulus following ESL disruption with hyaluronidase.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Constitutive retention and migration of monocytes and neutrophils within the glomerular microvasculature was unaltered by hyaluronidase. Consistent with this, inhibition of the hyaluronan-binding molecule CD44 also failed to modulate glomerular trafficking of these immune cells. To investigate the contribution of the ESL during acute inflammation, we induced glomerulonephritis via in situ immune complex deposition. This resulted in increases in glomerular retention of monocytes and neutrophils but did not induce marked reduction in the glomerular ESL. Furthermore, hyaluronidase treatment did not modify the prolonged retention of monocytes and neutrophils in the acutely inflamed glomerular microvasculature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These observations indicate that, despite evidence that the ESL has the capacity to inhibit leukocyte-endothelial cell interactions while also containing adhesive ligands for immune cells, neither of these functions modulate trafficking of monocytes and neutrophils in steady-state or acutely-inflamed glomeruli.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"30 7","pages":""},"PeriodicalIF":2.4,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12823","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10234592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mai Azuma, Shingo Kato, Kazuki Fukui, Nobuyuki Horita, Daisuke Utsunomiya
Background
Although microvascular dysfunction (MVD) is considered an essential pathophysiology in patients with heart failure with preserved ejection fraction (HFpEF), the frequency and prognostic impact of MVD are not fully understood. This meta-analysis evaluated the frequency of MVD in patients with HFpEF and its utility in risk stratification.
Materials and Methods
On May 26, 2022, a literature search was performed on PubMed, Web of Science, the Cochrane library, and Embase using the search terms such as “Heart failure with preserved ejection fraction,” “HFpEF,” “microvascular dysfunction,” and “MVD.” The prevalence of MVD in patients with HFpEF was calculated using the general inverse variance method. A comprehensive literature review was conducted to examine the association between MVD and prognosis in patients with HFpEF.
Results
Data pertaining to a total of 941 patients diagnosed with HFpEF were extracted from the collective pool of 9 studies. The results of the meta-analysis revealed that the frequency of MVD among patients with HFpEF was found to be 55.5% (95% CI: 34.8%–76.2%), with a substantial degree of heterogeneity (I2 = 98%, p for heterogeneity <.001). Among the five studies that provided data on the association between MVD and prognosis, a significant statistical association was observed in four of them.
Conclusions
This meta-analysis revealed that approximately 50% of patients diagnosed with HFpEF exhibited MVD. Moreover, the presence of MVD demonstrated significant prognostic implications in multiple studies conducted on patients with HFpEF. These findings strongly suggest that MVD plays a crucial role in the underlying pathophysiology of patients with HFpEF.
背景：尽管微血管功能障碍（MVD）被认为是射血分数保留（HFpEF）的心力衰竭患者的一种重要病理生理学，但MVD的频率和预后影响尚不完全清楚。这项荟萃分析评估了HFpEF患者MVD的频率及其在风险分层中的作用。材料和方法：2022年5月26日，在PubMed、Web of Science、Cochrane图书馆和Embase上使用“射血分数保留的心力衰竭”、“HFpEF”、“微血管功能障碍”和“MVD”等搜索词进行文献检索。使用通用逆方差法计算HFpEF患者的MVD患病率。对HFpEF患者的MVD与预后之间的关系进行了全面的文献综述。结果：从9项研究的集合中提取了941名诊断为HFpEF的患者的相关数据。荟萃分析结果显示，HFpEF患者的MVD发生率为55.5%（95%CI:34.8%-76.2%），具有显著的异质性（I2 = 98%，异质性为p结论：该荟萃分析显示，约50%的HFpEF患者表现出MVD。此外，在对HFpEF患者进行的多项研究中，MVD的存在显示出显著的预后影响。这些发现有力地表明，MVD在HFpEF患者的潜在病理生理学中起着至关重要的作用。
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Vibujithan Vigneshwaran, Christine Lauren Sy, Bruce H. Smaill, Gregory B. Sands, Nicolas P. Smith
Recent advances in tissue clearing and high‐throughput imaging have enabled the acquisition of extended‐volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets.
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