Pub Date : 2023-09-02DOI: 10.1007/s10456-023-09894-5
Xiaoming Wu, Jialan Shi
{"title":"Reply to “Embracing imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19”","authors":"Xiaoming Wu, Jialan Shi","doi":"10.1007/s10456-023-09894-5","DOIUrl":"10.1007/s10456-023-09894-5","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2023-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09894-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41188891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-28DOI: 10.1007/s10456-023-09895-4
Andrew C. Dudley, Arjan W. Griffioen
Following the process of vasculogenesis during development, angiogenesis generates new vascular structures through a variety of different mechanisms or modes. These different modes of angiogenesis involve, for example, increasing microvasculature density by sprouting of endothelial cells, splitting of vessels to increase vascular surface area by intussusceptive angiogenesis, fusion of capillaries to increase blood flow by coalescent angiogenesis, and the recruitment of non-endothelial cells by vasculogenic mimicry. The recent reporting on coalescent angiogenesis as a new mode of vessel formation warrants a brief overview of angiogenesis mechanisms to provide a more complete picture. The journal Angiogenesis is devoted to the delineation of the different modes and mechanisms that collectively dictate blood vessel formation, inhibition, and function in health and disease.
{"title":"The modes of angiogenesis: an updated perspective","authors":"Andrew C. Dudley, Arjan W. Griffioen","doi":"10.1007/s10456-023-09895-4","DOIUrl":"10.1007/s10456-023-09895-4","url":null,"abstract":"<div><p>Following the process of vasculogenesis during development, angiogenesis generates new vascular structures through a variety of different mechanisms or modes. These different modes of angiogenesis involve, for example, increasing microvasculature density by sprouting of endothelial cells, splitting of vessels to increase vascular surface area by intussusceptive angiogenesis, fusion of capillaries to increase blood flow by coalescent angiogenesis, and the recruitment of non-endothelial cells by vasculogenic mimicry. The recent reporting on coalescent angiogenesis as a new mode of vessel formation warrants a brief overview of angiogenesis mechanisms to provide a more complete picture. The journal <i>Angiogenesis</i> is devoted to the delineation of the different modes and mechanisms that collectively dictate blood vessel formation, inhibition, and function in health and disease.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41188893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-23DOI: 10.1007/s10456-023-09892-7
Timon Kuchler, Roman Günthner, Andrea Ribeiro, Renate Hausinger, Lukas Streese, Anna Wöhnl, Veronika Kesseler, Johanna Negele, Tarek Assali, Javier Carbajo-Lozoya, Maciej Lech, Heike Schneider, Kristina Adorjan, Hans Christian Stubbe, Henner Hanssen, Konstantin Kotilar, Bernhard Haller, Uwe Heemann, Christoph Schmaderer
{"title":"Correction: Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation","authors":"Timon Kuchler, Roman Günthner, Andrea Ribeiro, Renate Hausinger, Lukas Streese, Anna Wöhnl, Veronika Kesseler, Johanna Negele, Tarek Assali, Javier Carbajo-Lozoya, Maciej Lech, Heike Schneider, Kristina Adorjan, Hans Christian Stubbe, Henner Hanssen, Konstantin Kotilar, Bernhard Haller, Uwe Heemann, Christoph Schmaderer","doi":"10.1007/s10456-023-09892-7","DOIUrl":"10.1007/s10456-023-09892-7","url":null,"abstract":"","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09892-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10062002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tissue-resident vascular endothelial stem cells (VESCs), marked by expression of CD157, possess long-term repopulating potential and contribute to vascular regeneration and homeostasis in mice. Stem cell exhaustion is regarded as one of the hallmarks of aging and is being extensively studied in several types of tissue-resident stem cells; however, how aging affects VESCs has not been clarified yet. In the present study, we isolated VESCs from young and aged mice to compare their potential to differentiate into endothelial cells in vitro and in vivo. Here, we report that the number of liver endothelial cells (ECs) including VESCs was lower in aged (27–28 month-old) than young (2–3 month-old) mice. In vitro culture of primary VESCs revealed that the potential to generate ECs is impaired in aged VESCs isolated from liver and lung relative to young VESCs. Orthotopic transplantation of VESCs showed that aged VESCs and their progeny expand less efficiently than their young counterparts when transplanted into aged mice, but they are equally functional in young recipients. Gene expression analysis indicated that inflammatory signaling was more activated in aged ECs including VESCs. Using single-cell RNA sequencing data from the Tabula Muris Consortium, we show that T cells and monocyte/macrophage lineage cells including Kupffer cells are enriched in the aged liver. These immune cells produce IL-1β and several chemokines, suggesting the possible involvement of age-associated inflammation in the functional decline of VESCs with age.
{"title":"Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice","authors":"Shota Shimizu, Tomohiro Iba, Hisamichi Naito, Fitriana Nur Rahmawati, Hirotaka Konishi, Weizhen Jia, Fumitaka Muramatsu, Nobuyuki Takakura","doi":"10.1007/s10456-023-09891-8","DOIUrl":"10.1007/s10456-023-09891-8","url":null,"abstract":"<div><p>Tissue-resident vascular endothelial stem cells (VESCs), marked by expression of CD157, possess long-term repopulating potential and contribute to vascular regeneration and homeostasis in mice. Stem cell exhaustion is regarded as one of the hallmarks of aging and is being extensively studied in several types of tissue-resident stem cells; however, how aging affects VESCs has not been clarified yet. In the present study, we isolated VESCs from young and aged mice to compare their potential to differentiate into endothelial cells in vitro and in vivo. Here, we report that the number of liver endothelial cells (ECs) including VESCs was lower in aged (27–28 month-old) than young (2–3 month-old) mice. In vitro culture of primary VESCs revealed that the potential to generate ECs is impaired in aged VESCs isolated from liver and lung relative to young VESCs. Orthotopic transplantation of VESCs showed that aged VESCs and their progeny expand less efficiently than their young counterparts when transplanted into aged mice, but they are equally functional in young recipients. Gene expression analysis indicated that inflammatory signaling was more activated in aged ECs including VESCs. Using single-cell RNA sequencing data from the Tabula Muris Consortium, we show that T cells and monocyte/macrophage lineage cells including Kupffer cells are enriched in the aged liver. These immune cells produce IL-1β and several chemokines, suggesting the possible involvement of age-associated inflammation in the functional decline of VESCs with age.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09891-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41188886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-02DOI: 10.1007/s10456-023-09889-2
Chia Siang Kow, Dinesh Sangarran Ramachandram, Syed Shahzad Hasan
Imatinib, an ABL tyrosine-kinase inhibitor, shows promise in restoring endothelial barrier function in patients with COVID-19, thus, preventing cytokine leakage from the alveolar compartment to the systemic compartment. COVID-19 is characterized by an alveolar cytokine storm, and imatinib has been shown to strengthen the endothelial barrier and mitigate alveolar inflammatory responses by modulating NF-κB signaling. Incorporating imatinib into COVID-19 treatment strategies offers a novel approach to safeguard the endothelial barrier and address the complex pathophysiology of the disease, including its potential implications in long COVID. Given that endothelial dysfunction plays a central role in COVID-19 progression and long COVID development, protecting the endothelial barrier during acute infection is crucial in preventing the persistent endothelial dysfunction associated with long COVID.
{"title":"Embracing Imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19","authors":"Chia Siang Kow, Dinesh Sangarran Ramachandram, Syed Shahzad Hasan","doi":"10.1007/s10456-023-09889-2","DOIUrl":"10.1007/s10456-023-09889-2","url":null,"abstract":"<div><p>Imatinib, an ABL tyrosine-kinase inhibitor, shows promise in restoring endothelial barrier function in patients with COVID-19, thus, preventing cytokine leakage from the alveolar compartment to the systemic compartment. COVID-19 is characterized by an alveolar cytokine storm, and imatinib has been shown to strengthen the endothelial barrier and mitigate alveolar inflammatory responses by modulating NF-κB signaling. Incorporating imatinib into COVID-19 treatment strategies offers a novel approach to safeguard the endothelial barrier and address the complex pathophysiology of the disease, including its potential implications in long COVID. Given that endothelial dysfunction plays a central role in COVID-19 progression and long COVID development, protecting the endothelial barrier during acute infection is crucial in preventing the persistent endothelial dysfunction associated with long COVID.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2023-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41188888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-01DOI: 10.1007/s10456-023-09890-9
Aurélien Philippe, Sven Günther, Jeanne Rancic, Pauline Cavagna, Bertrand Renaud, Nicolas Gendron, Elie Mousseaux, Thông Hua-Huy, Guillaume Reverdito, Benjamin Planquette, Olivier Sanchez, Pascale Gaussem, Dominique Salmon, Jean-Luc Diehl, David M. Smadja
Background
Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19.
Objective
To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19.
Methods
Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT).
Results
The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement.
Conclusion
VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.
{"title":"VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients","authors":"Aurélien Philippe, Sven Günther, Jeanne Rancic, Pauline Cavagna, Bertrand Renaud, Nicolas Gendron, Elie Mousseaux, Thông Hua-Huy, Guillaume Reverdito, Benjamin Planquette, Olivier Sanchez, Pascale Gaussem, Dominique Salmon, Jean-Luc Diehl, David M. Smadja","doi":"10.1007/s10456-023-09890-9","DOIUrl":"10.1007/s10456-023-09890-9","url":null,"abstract":"<div><h3>Background</h3><p>Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19.</p><h3>Objective</h3><p>To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19.</p><h3>Methods</h3><p>Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT).</p><h3>Results</h3><p>The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (<i>n</i> = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement.</p><h3>Conclusion</h3><p>VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-28DOI: 10.1007/s10456-023-09885-6
Timon Kuchler, Roman Günthner, Andrea Ribeiro, Renate Hausinger, Lukas Streese, Anna Wöhnl, Veronika Kesseler, Johanna Negele, Tarek Assali, Javier Carbajo-Lozoya, Maciej Lech, Heike Schneider, Kristina Adorjan, Hans Christian Stubbe, Henner Hanssen, Konstantin Kotilar, Bernhard Haller, Uwe Heemann, Christoph Schmaderer
Background
Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.
Methods
In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204).
Measurements and main results
PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = − 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.
Conclusion
Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.
Trial registration
This study was previously registered at ClinicalTrials (“All Eyes on PCS—Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552).
Graphical abstract
Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com