Sara Z. Jamal, Blake W. Dieckmann, Gary W. McCollum, John S. Penn, Ashwath Jayagopal, MD Imam Uddin
Purpose
To develop a reliable method to generate a mouse model of branch retinal artery occlusion (BRAO) using laser-induced thrombosis of a major artery in the mouse retina. Also, to develop a reliable method to detect retinal hypoxia as predictive biomarker for the risk of neuronal cell damage in BRAO.
Methods
A reliable and reproducible model of laser-induced BRAO was developed in mouse retina using Rose Bengal. To characterize retinal hypoxia in BRAO, pimonidazole immunostaining and HYPOX-4 molecular imaging methods were used. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was used to characterize neuronal cell damage in the BRAO retina. Expression of mRNA in retinal tissues from BRAO and age-matched control retinas were analyzed using qRT-PCR.
Results
Occlusion of a branch retinal artery near the optic nerve head (ONH) caused a pattern of retinal tissue hypoxia covering about 12.5% of the entire retina. TUNEL-positive cells were localized in all layers in BRAO retinal tissue cross sections. In addition, qRT-PCR data analysis suggests that BRAO is associated with both inflammation and hypoxia.
Conclusions
This study provides a reliable method for BRAO in mouse retina and demonstrates the utility of molecular imaging method to detect retinal hypoxia as predictive biomarker for the risk of neuronal cell damage in BRAO. In addition, our data suggest that BRAO retinas are associated with inflammation and also associated with hypoxia-related neuronal cell damage.
Perspectives
Imaging areas of retinal hypoxia may provide accurate diagnosis, evaluating retinal tissue injury from BRAO.
{"title":"Imaging Hypoxia to Predict Primary Neuronal Cell Damage in Branch Retinal Artery Occlusion","authors":"Sara Z. Jamal, Blake W. Dieckmann, Gary W. McCollum, John S. Penn, Ashwath Jayagopal, MD Imam Uddin","doi":"10.1111/micc.12883","DOIUrl":"10.1111/micc.12883","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>To develop a reliable method to generate a mouse model of branch retinal artery occlusion (BRAO) using laser-induced thrombosis of a major artery in the mouse retina. Also, to develop a reliable method to detect retinal hypoxia as predictive biomarker for the risk of neuronal cell damage in BRAO.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A reliable and reproducible model of laser-induced BRAO was developed in mouse retina using Rose Bengal. To characterize retinal hypoxia in BRAO, pimonidazole immunostaining and HYPOX-4 molecular imaging methods were used. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was used to characterize neuronal cell damage in the BRAO retina. Expression of mRNA in retinal tissues from BRAO and age-matched control retinas were analyzed using qRT-PCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Occlusion of a branch retinal artery near the optic nerve head (ONH) caused a pattern of retinal tissue hypoxia covering about 12.5% of the entire retina. TUNEL-positive cells were localized in all layers in BRAO retinal tissue cross sections. In addition, qRT-PCR data analysis suggests that BRAO is associated with both inflammation and hypoxia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study provides a reliable method for BRAO in mouse retina and demonstrates the utility of molecular imaging method to detect retinal hypoxia as predictive biomarker for the risk of neuronal cell damage in BRAO. In addition, our data suggest that BRAO retinas are associated with inflammation and also associated with hypoxia-related neuronal cell damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Perspectives</h3>\u0000 \u0000 <p>Imaging areas of retinal hypoxia may provide accurate diagnosis, evaluating retinal tissue injury from BRAO.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12883","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109154","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}
Jade L. Taylor, Miguel Martin-Aragon Baudel, Madeline Nieves-Cintron, Manuel F. Navedo
This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression.
这篇综述论文探讨了血管离子通道在调节脑动脉功能中的关键作用，并研究了阿尔茨海默病（AD）对这些过程的影响。血管离子通道是控制脑动脉血管张力、血流量和内皮功能的基础。这些通道的功能失调会导致大脑自动调节功能受损，从而引发脑血管病变。以淀粉样β（Aβ）斑块和神经纤维缠结的积累为特征的注意力缺失症与血管异常（包括血管离子通道活性的改变）的关系日益密切。在此，我们简要回顾了血管离子通道在脑血流控制和神经血管耦合中的作用。然后，我们研究了 AD 的血管缺陷、目前对 AD 病理如何影响血管离子通道功能的理解，以及这些变化如何可能导致脑血流受损和神经退行性过程。最后，我们提出了未来的展望和结论。了解这一主题非常重要，因为离子通道可能是改善脑血管健康和缓解 AD 进展的潜在治疗靶点。
{"title":"Vascular Function and Ion Channels in Alzheimer's Disease","authors":"Jade L. Taylor, Miguel Martin-Aragon Baudel, Madeline Nieves-Cintron, Manuel F. Navedo","doi":"10.1111/micc.12881","DOIUrl":"10.1111/micc.12881","url":null,"abstract":"<p>This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression.</p>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12881","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080738","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}
X. Zhao, C. Schalkwijk, A. Kroon, M. T. Schram, C. Stehouwer, A. Houben
Objective
Diabetes can lead to microvascular complications such as diabetic neuropathy, nephropathy, and retinopathy. Hyperglycemia may initiate microvascular function impairment early in the course of diabetes, even prior to its clinical establishment during the pre-diabetes stage. Microvascular vasomotion, that is, the rhythmic arteriolar constriction and dilation, is an important function that regulates oxygen and nutrient delivery within the tissue and regulates peripheral resistance. Using laser Doppler flowmetry (LDF), vasomotion in skin microcirculation can be measured as flowmotion. Changes in flowmotion have been shown in individuals with obesity, and type 1 or type 2 diabetes mellitus. However, no data are available on associations between hyperglycemia and flowmotion in the general population. Our aim was to study whether measures of hyperglycemia were associated with different components of skin microvascular flowmotion (SMF) in a population-based cohort (The Maastricht Study).
Methods
Data from 7293 participants of The Maastricht Study were used. SMF was measured using LDF. Endothelial, neurogenic and myogenic component SMF power were used as dependent variables. We investigated the associations of glucose metabolism status (normal glucose metabolism, prediabetes, and type 2 diabetes mellitus), measures of hyperglycemia (fasting plasma glucose [FPG], 2-h post-load glucose [2 h-PG], HbA1c, advanced glycation end-products [AGEs] assessed as skin autofluorescence [SAF]), and indices of glucose variability (incremental glucose peak [IGP] and continuous glucose monitoring [CGM] -assessed as standard deviation [SD]) with each component of SMF power. We used linear regression analyses with adjustments for confounders, and trend analyses.
Results
We observed consistent negative associations between HbA1c levels and all three (endothelial, neurogenic, and myogenic) skin microvascular flowmotion (SMF) powers in the additionally adjusted model. Similarly, in the conservative model, we found that multiple hyperglycemia metrics such as GMS trend, PreD, T2DM, FPG, 2 h-PG, and HbA1c were consistently negatively associated with all three SMF powers.
Conclusions
We showed that skin microvascular flowmotion is reduced in individuals with (pre)diabetes. In addition, different measures of hyperglycemia are negatively associated with skin microvascular flowmotion.
{"title":"Different Measures of Hyperglycemia Are Negatively Associated With Skin Microvascular Flowmotion: The Maastricht Study","authors":"X. Zhao, C. Schalkwijk, A. Kroon, M. T. Schram, C. Stehouwer, A. Houben","doi":"10.1111/micc.12882","DOIUrl":"10.1111/micc.12882","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Diabetes can lead to microvascular complications such as diabetic neuropathy, nephropathy, and retinopathy. Hyperglycemia may initiate microvascular function impairment early in the course of diabetes, even prior to its clinical establishment during the pre-diabetes stage. Microvascular vasomotion, that is, the rhythmic arteriolar constriction and dilation, is an important function that regulates oxygen and nutrient delivery within the tissue and regulates peripheral resistance. Using laser Doppler flowmetry (LDF), vasomotion in skin microcirculation can be measured as flowmotion. Changes in flowmotion have been shown in individuals with obesity, and type 1 or type 2 diabetes mellitus. However, no data are available on associations between hyperglycemia and flowmotion in the general population. Our aim was to study whether measures of hyperglycemia were associated with different components of skin microvascular flowmotion (SMF) in a population-based cohort (The Maastricht Study).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data from 7293 participants of The Maastricht Study were used. SMF was measured using LDF. Endothelial, neurogenic and myogenic component SMF power were used as dependent variables. We investigated the associations of glucose metabolism status (normal glucose metabolism, prediabetes, and type 2 diabetes mellitus), measures of hyperglycemia (fasting plasma glucose [FPG], 2-h post-load glucose [2 h-PG], HbA1c, advanced glycation end-products [AGEs] assessed as skin autofluorescence [SAF]), and indices of glucose variability (incremental glucose peak [IGP] and continuous glucose monitoring [CGM] -assessed as standard deviation [SD]) with each component of SMF power. We used linear regression analyses with adjustments for confounders, and trend analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed consistent negative associations between HbA1c levels and all three (endothelial, neurogenic, and myogenic) skin microvascular flowmotion (SMF) powers in the additionally adjusted model. Similarly, in the conservative model, we found that multiple hyperglycemia metrics such as GMS trend, PreD, T2DM, FPG, 2 h-PG, and HbA1c were consistently negatively associated with all three SMF powers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We showed that skin microvascular flowmotion is reduced in individuals with (pre)diabetes. In addition, different measures of hyperglycemia are negatively associated with skin microvascular flowmotion.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12882","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017961","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}
Intragastric administration of ninjin'yoeito (NYT), a traditional Japanese herbal medicine, reportedly prevents the decrease in baseline cerebral blood flow (CBF) in the cortex following gastric administration of water. We investigated the effect of NYT on baseline and dynamic changes in cerebral cortical arteriole diameter.
Methods
Urethane-anesthetized mice were intragastrically administered 1 g/kg NYT or distilled water (DW). The artery in the left parietal cortex was imaged using two-photon microscopy. The baseline diameter of penetrating arterioles was measured before and 50–60 min after administration. Dynamic CBF and arteriole diameter changes before, during, and after transient occlusion of the left common carotid artery were measured approximately 10 min after administration.
Results
DW decreased the baseline diameter of the penetrating arterioles, whereas NYT did not. During occlusion, the increase in penetrating arteriole diameter was comparable for DW and NYT; however, during reperfusion, the return to preocclusion diameter was slower for NYT than DW. Laser-speckle contrast imaging confirmed that CBF, although comparable during occlusion, was higher during reperfusion for NYT than DW.
Conclusions
These results suggest that NYT attenuates vasoconstriction in penetrating arterioles after intragastric administration and during cerebral reperfusion, contributing to CBF regulation.
目的据报道，胃内注射日本传统草药 "忍者"（NYT）可防止胃内注射水后大脑皮层基线脑血流量（CBF）的减少。我们研究了NYT对大脑皮层动脉直径基线和动态变化的影响：方法：给尿烷麻醉的小鼠胃内注射 1 g/kg NYT 或蒸馏水（DW）。使用双光子显微镜对左顶叶皮层的动脉进行成像。在给药前和给药后 50-60 分钟测量穿透动脉血管的基线直径。给药后约 10 分钟，测量左侧颈总动脉瞬时闭塞前、闭塞过程中和闭塞后的动态 CBF 和动脉血管直径变化：结果：DW降低了穿透性动脉血管的基线直径，而NYT则没有。在闭塞过程中，DW 和 NYT 的穿通动脉直径增加速度相当；但在再灌注过程中，NYT 恢复到闭塞前直径的速度比 DW 慢。激光斑点对比成像证实，虽然闭塞期间的 CBF 不相上下，但再灌注期间 NYT 的 CBF 要高于 DW：这些结果表明，NYT可减轻胃内给药后和脑再灌注期间穿透性动脉血管的血管收缩，从而有助于调节CBF。
{"title":"Ninjin'yoeito Modulates Baseline and Reperfusion-Induced Changes in the Arteriole Diameter and Blood Flow in the Cerebral Cortex of Anesthetized Mice","authors":"Nobuhiro Watanabe, Kaori Iimura, Harumi Hotta","doi":"10.1111/micc.12880","DOIUrl":"10.1111/micc.12880","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Intragastric administration of ninjin'yoeito (NYT), a traditional Japanese herbal medicine, reportedly prevents the decrease in baseline cerebral blood flow (CBF) in the cortex following gastric administration of water. We investigated the effect of NYT on baseline and dynamic changes in cerebral cortical arteriole diameter.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Urethane-anesthetized mice were intragastrically administered 1 g/kg NYT or distilled water (DW). The artery in the left parietal cortex was imaged using two-photon microscopy. The baseline diameter of penetrating arterioles was measured before and 50–60 min after administration. Dynamic CBF and arteriole diameter changes before, during, and after transient occlusion of the left common carotid artery were measured approximately 10 min after administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DW decreased the baseline diameter of the penetrating arterioles, whereas NYT did not. During occlusion, the increase in penetrating arteriole diameter was comparable for DW and NYT; however, during reperfusion, the return to preocclusion diameter was slower for NYT than DW. Laser-speckle contrast imaging confirmed that CBF, although comparable during occlusion, was higher during reperfusion for NYT than DW.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results suggest that NYT attenuates vasoconstriction in penetrating arterioles after intragastric administration and during cerebral reperfusion, contributing to CBF regulation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909940","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}
Catharina Elizabeth Myburgh-Jacobsz, Shani Botha-Le Roux, Konstantin Kotliar, Annemarie Wentzel, Adriaan Jacobs, Patrick De Boever, Nandu Goswami, Hans Strijdom, Wayne Smith
Objectives
The effects of HIV and antiretroviral therapy (ART) on microvascular function are poorly explored. We compared retinal vessel functional responses to flicker light-induced provocation (FLIP) in people living with HIV (PLWH) and people living without HIV (PLWoutH).
Methods
We included 115 PLWH and 51 PLWoutH with a median age of 41 years. Treated PLWH received similar first-line fixed-dose combination ART. Clinical characteristics and retinal vessels functional responses to FLIP were compared in (a) PLWH and PLWoutH; and (b) PLWH groups stratified by the median of (i) CD4-count (511 cells/mm3), (ii) viral load (50 copies/mL), and (iii) ART duration (57.6 months).
Results
PLWH were older, smoked more, and had a lower prevalence of hypertension than PLWoutH (p < 0.05). Almost 64% of PLWH were infected for more than 5 years. Retinal vessel responses to FLIP were similar between PLWH and PLWoutH after taking confounders into account. In addition, PLWH subgroups stratified according to immuno-virological status by CD4-count, viral load, and ART duration showed no differences in retinal vessel responses to FLIP.
Conclusion
Living with HIV and receiving ART were not associated with altered microvascular function as assessed with dynamic retinal vessel analysis in a South African case–control study.
{"title":"Retinal Vessel Functional Responses in South Africans Living With and Without HIV: The EndoAfrica-NWU Study","authors":"Catharina Elizabeth Myburgh-Jacobsz, Shani Botha-Le Roux, Konstantin Kotliar, Annemarie Wentzel, Adriaan Jacobs, Patrick De Boever, Nandu Goswami, Hans Strijdom, Wayne Smith","doi":"10.1111/micc.12878","DOIUrl":"10.1111/micc.12878","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The effects of HIV and antiretroviral therapy (ART) on microvascular function are poorly explored. We compared retinal vessel functional responses to flicker light-induced provocation (FLIP) in people living with HIV (PLWH) and people living without HIV (PLWoutH).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 115 PLWH and 51 PLWoutH with a median age of 41 years. Treated PLWH received similar first-line fixed-dose combination ART. Clinical characteristics and retinal vessels functional responses to FLIP were compared in (a) PLWH and PLWoutH; and (b) PLWH groups stratified by the median of (i) CD4-count (511 cells/mm<sup>3</sup>), (ii) viral load (50 copies/mL), and (iii) ART duration (57.6 months).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PLWH were older, smoked more, and had a lower prevalence of hypertension than PLWoutH (<i>p</i> < 0.05). Almost 64% of PLWH were infected for more than 5 years. Retinal vessel responses to FLIP were similar between PLWH and PLWoutH after taking confounders into account. In addition, PLWH subgroups stratified according to immuno-virological status by CD4-count, viral load, and ART duration showed no differences in retinal vessel responses to FLIP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Living with HIV and receiving ART were not associated with altered microvascular function as assessed with dynamic retinal vessel analysis in a South African case–control study.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897774","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}
To clarify the effect of growth and advancing age on lymphatic capillarization in rat skeletal muscles, we examined the histological and biochemical changes of lymphatic capillaries in different fiber types of skeletal muscles across juvenile, young, and middle-aged generations.
Methods
We collected the tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. Immunohistochemical staining using LYVE-1 and CD31 markers was used for lymphatic and blood capillaries, respectively. Real-time PCR was used to analyze mRNA expression of lymphangiogenic factors.
Results
The density of LYVE-1-positive lymphatic capillaries in the muscles peaked during the juvenile period and subsequently decreased with increasing age. In contrast to blood capillaries, fast-twitch dominant muscles (i.e., TA and EDL) exhibited an age-related decrease in lymphatic capillaries. Similar to blood capillaries, lymphatic capillaries were abundant in SOL, a slow-twitch dominant muscle, which showed less susceptibility to age-related lymphatic decline. The mRNA expression of lymphangiogenic factors was significantly upregulated in SOL and decreased in all muscles of middle-aged rats.
Conclusions
The age-related decrease of lymphatic capillaries in fast-twitch muscles might be associated with age-related muscle atrophy.
方法 我们采集了大鼠胫骨前肌（TA）、趾长伸肌（EDL）和比目鱼肌（SOL）。分别使用 LYVE-1 和 CD31 标记对淋巴管和毛细血管进行免疫组化染色。结果肌肉中 LYVE-1 阳性淋巴毛细血管的密度在幼年期达到高峰，随后随着年龄的增长而下降。与血毛细血管不同，快肌优势肌肉（即 TA 和 EDL）的淋巴毛细血管随年龄增长而减少。与血毛细血管类似，淋巴毛细血管在 SOL 肌肉中也很丰富，SOL 肌肉是一种慢速运动优势肌肉，其淋巴衰退与年龄有关的敏感性较低。淋巴管生成因子的 mRNA 表达在 SOL 中显著上调，而在中年大鼠的所有肌肉中均有所下降。
{"title":"Lymphatic Capillarization in Different Fiber Types of Rat Skeletal Muscles With Growth and Age","authors":"Yoshikazu Taketa, Keigo Tamakoshi, Kazuki Hotta, Shutaro Maki, Toru Taguchi, Hideaki Takahashi","doi":"10.1111/micc.12879","DOIUrl":"10.1111/micc.12879","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To clarify the effect of growth and advancing age on lymphatic capillarization in rat skeletal muscles, we examined the histological and biochemical changes of lymphatic capillaries in different fiber types of skeletal muscles across juvenile, young, and middle-aged generations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We collected the tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. Immunohistochemical staining using LYVE-1 and CD31 markers was used for lymphatic and blood capillaries, respectively. Real-time PCR was used to analyze mRNA expression of lymphangiogenic factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The density of LYVE-1-positive lymphatic capillaries in the muscles peaked during the juvenile period and subsequently decreased with increasing age. In contrast to blood capillaries, fast-twitch dominant muscles (i.e., TA and EDL) exhibited an age-related decrease in lymphatic capillaries. Similar to blood capillaries, lymphatic capillaries were abundant in SOL, a slow-twitch dominant muscle, which showed less susceptibility to age-related lymphatic decline. The mRNA expression of lymphangiogenic factors was significantly upregulated in SOL and decreased in all muscles of middle-aged rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The age-related decrease of lymphatic capillaries in fast-twitch muscles might be associated with age-related muscle atrophy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141784574","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}
Keqing Li, Yuan Li, Yinghong Chen, Tangting Chen, Yan Yang, Pengyun Li
Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K+ channels, Ca2+ permeable channels, and Na+ channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel-targeted compounds in treating refractory hypotension in shock.
{"title":"Ion Channels Remodeling in the Regulation of Vascular Hyporesponsiveness During Shock","authors":"Keqing Li, Yuan Li, Yinghong Chen, Tangting Chen, Yan Yang, Pengyun Li","doi":"10.1111/micc.12874","DOIUrl":"10.1111/micc.12874","url":null,"abstract":"<div>\u0000 \u0000 <p>Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K<sup>+</sup> channels, Ca<sup>2+</sup> permeable channels, and Na<sup>+</sup> channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel-targeted compounds in treating refractory hypotension in shock.</p>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620403","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}
Abnormal tumor vascular network contributes to aberrant blood perfusion and reduced oxygenation in tumors, which lead to poor efficacy of chemotherapy and radiotherapy. We aimed to explore the effects of the tumor-derived exosomes (TDEs) and C188-9 (a small molecule inhibitor of signal transducer and activator of transcription 3, STAT3) on tumor microvascular hemodynamics and determine which blood flow oscillations for various frequency intervals are responsible for these changes.
Methods
Microvascular hemodynamics parameters were recorded using a PeriFlux 6000 EPOS system in tumor surface in a nude mouse subcutaneous xenograft model. Oscillations of laser Doppler flowmetry (LDF) signal were investigated by wavelet transform analysis.
Results
TDEs facilitated tumor growth at least partially was associated with increasing blood flow in smaller vessels with lower speed and decreasing the blood flow at larger vessels with higher speed. Lower oxyhemoglobin saturation (SO2) on tumor surface was aggravated by TDEs, and C188-9 treatment significantly alleviated this decrease. Wavelet transform spectral analysis revealed that TDEs increased the amplitude of oscillations in four frequency intervals related to endothelial (NO-dependent and -independent), myogenic and neurogenic activities, and C188-9 had no effect on this increase.
Conclusions
TDEs facilitated tumor growth partially was associated with increasing blood flow in distributing vessels, reducing blood perfusion in larger vessels, and lowering SO2 on tumor surface. Enhanced vascular smooth muscle, endothelial and neurogenic activities occurred in tumor superficial zone.
{"title":"Tumor-Derived Exosomes Promote Tumor Growth Through Modulating Microvascular Hemodynamics in a Human Ovarian Cancer Xenograft Model","authors":"Qin Wang, Xiaoyan Zhang, Bingwei Li, Xueting Liu, Ailing Li, Hongwei Li, Xiaohua Shi, Jianqun Han","doi":"10.1111/micc.12876","DOIUrl":"10.1111/micc.12876","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Abnormal tumor vascular network contributes to aberrant blood perfusion and reduced oxygenation in tumors, which lead to poor efficacy of chemotherapy and radiotherapy. We aimed to explore the effects of the tumor-derived exosomes (TDEs) and C188-9 (a small molecule inhibitor of signal transducer and activator of transcription 3, STAT3) on tumor microvascular hemodynamics and determine which blood flow oscillations for various frequency intervals are responsible for these changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Microvascular hemodynamics parameters were recorded using a PeriFlux 6000 EPOS system in tumor surface in a nude mouse subcutaneous xenograft model. Oscillations of laser Doppler flowmetry (LDF) signal were investigated by wavelet transform analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TDEs facilitated tumor growth at least partially was associated with increasing blood flow in smaller vessels with lower speed and decreasing the blood flow at larger vessels with higher speed. Lower oxyhemoglobin saturation (SO<sub>2</sub>) on tumor surface was aggravated by TDEs, and C188-9 treatment significantly alleviated this decrease. Wavelet transform spectral analysis revealed that TDEs increased the amplitude of oscillations in four frequency intervals related to endothelial (NO-dependent and -independent), myogenic and neurogenic activities, and C188-9 had no effect on this increase.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>TDEs facilitated tumor growth partially was associated with increasing blood flow in distributing vessels, reducing blood perfusion in larger vessels, and lowering SO<sub>2</sub> on tumor surface. Enhanced vascular smooth muscle, endothelial and neurogenic activities occurred in tumor superficial zone.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616787","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}
Mir Md Nasim Hossain, Nien-Wen Hu, Ali Kazempour, Walter L. Murfee, Peter Balogh
Objective
Tortuous microvessels are characteristic of microvascular remodeling associated with numerous physiological and pathological scenarios. Three-dimensional (3D) hemodynamics in tortuous microvessels influenced by red blood cells (RBCs), however, are largely unknown, and important questions remain. Is blood viscosity influenced by vessel tortuosity? How do RBC dynamics affect wall shear stress (WSS) patterns and the near-wall cell-free layer (CFL) over a range of conditions? The objective of this work was to parameterize hemodynamic characteristics unique to a tortuous microvessel.
Methods
RBC-resolved simulations were performed using an immersed boundary method-based 3D fluid dynamics solver. A representative tortuous microvessel was selected from a stimulated angiogenic network obtained from imaging of the rat mesentery and digitally reconstructed for the simulations. The representative microvessel was a venule with a diameter of approximately 20 μm. The model assumes a constant diameter along the vessel length and does not consider variations due to endothelial cell shapes or the endothelial surface layer.
Results
Microvessel tortuosity was observed to increase blood apparent viscosity compared to a straight tube by up to 26%. WSS spatial variations in high curvature regions reached 23.6 dyne/cm2 over the vessel cross-section. The magnitudes of WSS and CFL thickness variations due to tortuosity were strongly influenced by shear rate and negligibly influenced by tube hematocrit levels.
Conclusions
New findings from this work reveal unique tortuosity-dependent hemodynamic characteristics over a range of conditions. The results provide new thought-provoking information to better understand the contribution of tortuous vessels in physiological and pathological processes and help improve reduced-order models.
{"title":"Hemodynamic Characteristics of a Tortuous Microvessel Using High-Fidelity Red Blood Cell Resolved Simulations","authors":"Mir Md Nasim Hossain, Nien-Wen Hu, Ali Kazempour, Walter L. Murfee, Peter Balogh","doi":"10.1111/micc.12875","DOIUrl":"10.1111/micc.12875","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Tortuous microvessels are characteristic of microvascular remodeling associated with numerous physiological and pathological scenarios. Three-dimensional (3D) hemodynamics in tortuous microvessels influenced by red blood cells (RBCs), however, are largely unknown, and important questions remain. Is blood viscosity influenced by vessel tortuosity? How do RBC dynamics affect wall shear stress (WSS) patterns and the near-wall cell-free layer (CFL) over a range of conditions? The objective of this work was to parameterize hemodynamic characteristics unique to a tortuous microvessel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>RBC-resolved simulations were performed using an immersed boundary method-based 3D fluid dynamics solver. A representative tortuous microvessel was selected from a stimulated angiogenic network obtained from imaging of the rat mesentery and digitally reconstructed for the simulations. The representative microvessel was a venule with a diameter of approximately 20 μm. The model assumes a constant diameter along the vessel length and does not consider variations due to endothelial cell shapes or the endothelial surface layer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Microvessel tortuosity was observed to increase blood apparent viscosity compared to a straight tube by up to 26%. WSS spatial variations in high curvature regions reached 23.6 dyne/cm<sup>2</sup> over the vessel cross-section. The magnitudes of WSS and CFL thickness variations due to tortuosity were strongly influenced by shear rate and negligibly influenced by tube hematocrit levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>New findings from this work reveal unique tortuosity-dependent hemodynamic characteristics over a range of conditions. The results provide new thought-provoking information to better understand the contribution of tortuous vessels in physiological and pathological processes and help improve reduced-order models.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 7","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580209","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}
Intravascular lymphatic valves often occur in proximity to vessel junctions. It is commonly held that disturbed flow at junctions is responsible for accumulation of valve-forming cells (VFCs) at these locations as the initial step in valve creation, and the one which explains the association with these sites. However, evidence in favor is largely limited to cell culture experiments.
Methods
We acquired images of embryonic lymphatic vascular networks from day E16.5, when VFC accumulation has started but the developing valve has not yet altered the local vessel geometry, stained for Prox1, which co-localizes with Foxc2. Using finite-element computational fluid mechanics, we simulated the flow through the networks, under conditions appropriate to this early development stage. Then we correlated the Prox1 distributions with the distributions of simulated fluid shear and shear stress gradient.
Results
Across a total of 16 image sets, no consistent correlation was found between Prox1 distribution and the local magnitude of fluid shear, or its positive or negative gradient.
Conclusions
This, the first direct semi-empirical test of the localization hypothesis to interrogate the tissue from in vivo at the critical moment of development, does not support the idea that a feature of the local flow determines valve localization.
{"title":"Fluid-Dynamic Modeling of Flow in Embryonic Tissue Indicates That Lymphatic Valve Location Is Not Consistently Determined by the Local Fluid Shear or Its Gradient","authors":"Christopher D. Bertram, Charlie Macaskill","doi":"10.1111/micc.12873","DOIUrl":"10.1111/micc.12873","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Intravascular lymphatic valves often occur in proximity to vessel junctions. It is commonly held that disturbed flow at junctions is responsible for accumulation of valve-forming cells (VFCs) at these locations as the initial step in valve creation, and the one which explains the association with these sites. However, evidence in favor is largely limited to cell culture experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We acquired images of embryonic lymphatic vascular networks from day E16.5, when VFC accumulation has started but the developing valve has not yet altered the local vessel geometry, stained for Prox1, which co-localizes with Foxc2. Using finite-element computational fluid mechanics, we simulated the flow through the networks, under conditions appropriate to this early development stage. Then we correlated the Prox1 distributions with the distributions of simulated fluid shear and shear stress gradient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Across a total of 16 image sets, no consistent correlation was found between Prox1 distribution and the local magnitude of fluid shear, or its positive or negative gradient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This, the first direct semi-empirical test of the localization hypothesis to interrogate the tissue from in vivo at the critical moment of development, does not support the idea that a feature of the local flow determines valve localization.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":"31 6","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492589","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}
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