Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
Background Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis. Objectives To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening. Methods Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission. Results Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers. Conclusion Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
Objectives-The importance of PAR-1 in blood vessel development has been demonstrated in knockout mice. As endothelial progenitor cells (EPCs) are involved in postnatal vasculogenesis, we examined whether they express PAR-1 and whether stimulation by the peptide SFLLRN modulates their angiogenic properties. Methods and Results-EPC expanded from human CD34ϩ cord blood cells expressed PAR-1. PAR-1 activation induced EPC proliferation in a concentration-dependent manner far more potently than that of human umbilical vein endothelial cells. PAR-1 activation also enhanced actin reorganization, promoting both spontaneous migration in a Boyden chamber assay and migration toward SDF-1 and VEGF. As shown by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR), EPC stimulation by SFLLRN significantly enhanced the mRNA expression of SDF-1 and its receptor CXCR-4. PAR-1 activation also increased CXCR4 expression on EPC and induced SDF-1 secretion, leading to autocrine stimulation. PAR-1 stimulation by SFLLRN also increased the formation of capillary-like structures by EPC in Matrigel, and this effect was abrogated by anti-CXCR-4, anti-SDF-1, and MEK inhibitor pretreatment. 3,4 Besides its contribution to hemostasis, thrombin is involved in angiogenesis. Mouse models with impaired thrombin generation display altered vascular development. 5 The main thrombin receptor on vascular cells, PAR-1, is a protease-activated G protein-coupled receptor specifically cleaved by thrombin at its extracellular N-terminus. The amino-terminal sequence thereby unmasked acts as a tethered ligand, triggering a rapid response that can be reproduced by a specific hexapeptide (SFLLRN). PAR-1 Ϫ/Ϫ knockout mice show partial embryonic lethality, 6 pointing to a specific developmental role of PAR-1. Moreover, PAR-1 activation on mature endothelial cells regulates many aspects of endothelial cell biology, such as induction of vascular endothelial growth factor (VEGF) synthesis 7 and upregulation of the main VEGF receptor VEGFR-2. 8 The thrombin receptoractivating peptide SFLLRN, which acts as an agonist for PAR-1, was also reported to promote capillary network formation in an in vivo Matrigel plug model. 9 Interestingly, the antiangiogenic properties of thalidomide have been linked to inhibition of PAR-1 gene expression. 10 PAR-1 activation by thrombin promotes tumor progression and metastasis, both effects being related to new capillary formation. 11 However, the mechanism underlying the proangiogenic effect of PAR-1 activation is unclear. Conclusions-HumanIn this study we examined the expression and function of PAR-1 by human late EPCs expanded from cord blood CD34ϩ cells. MethodsAn expanded methods section is available online at http://atvb.ahajournals.org. EPC CultureCD34ϩ-derived EPC from cord blood were obtained by density gradient centrifugation with Histopaque 1077 (Sigma, St. Louis, Mo) as previously described. 12 Isolated mononuclear cells were resuspended in endothelial growth medium-2 (EGM-2) (Clonetics) composed ...
Objective-We examined whether plasma levels of angiogenic factors are altered in plasma of patients with peripheral arterial disease (PAD) and whether these factors affect endothelial progenitor cell-induced angiogenesis. Methods and Results-Plasma was collected from 184 patients with PAD and 330 age-matched healthy controls. Vascular endothelial growth factor and placental growth factor concentrations did not differ between the groups, whereas we found a linear correlation between PAD disease and thrombospondin (TSP)-1 plasma level. TSP-1 was expressed in newly formed vessels in PAD patients having received local injections of bone marrow mononuclear cells. To analyze the functional role of TSP-1 during neoangiogenesis, we used a Matrigel-plug assay and showed that vascularization of implanted Matrigel-plugs was increased in TSP-1 Ϫ/Ϫ mice. Moreover, injections of TSP-1 in C57Bl6/J mice after hindlimb ischemia induced a significant decrease of blood flow recovery. To investigate the effects of TSP-1 on human endothelial colony-forming cell (ECFC) angiogenic potential, recombinant human TSP-1 and a small interfering RNA were used. In vitro, TSP-1 N-terminal part significantly enhanced ECFC adhesion, whereas recombinant human TSP-1 had a negative effect on ECFC angiogenic potential. This effect, mediated by CD47 binding, modulated stromal cell-derived factor 1/CXC chemokine receptor 4 pathway. Key Words: angiogenesis Ⅲ arterial thrombosis Ⅲ endothelial progenitor cells P eripheral arterial disease (PAD), characterized by atherosclerosis of the lower extremities, affects up to 15% of people older than 55 years. 1 The main clinical manifestations of PAD are intermittent claudication and critical limb ischemia (CLI). Intermittent claudication is characterized by reproducible pain on exertion that is relieved by rest. CLI is the most severe form of PAD and is characterized by the inability of arterial blood flow to meet the metabolic demands of resting muscle or tissue, resulting in rest pain and/or tissue necrosis and frequently necessitating amputation. Currently, PAD diagnosis is based on the ankle-brachial systolic pressure index (ABI), but the ABI is a poor marker of PAD severity. There are no other reliable diagnostic tests for PAD, and new biomarkers would therefore be useful. Conclusion-TSP-1 is a potential biomarker of PAD and ECFC-induced angiogenesisAtherosclerosis induces occlusion of the arterial tree and tissue hypoxia, which is a strong stimulus for angiogenesis. Collateral vessels develop physiologically in patients with CLI, mainly driven by an enhanced angiogenic response. 2 However, the capacity of this compensatory mechanism is rapidly exceeded, and normal flow is not restored. Autologous endothelial progenitor cells (EPCs) are candidates for angiogenic therapy. Because of their scarcity in human samples, EPCs have been characterized by culture methods. At least 2 populations of EPCs have been described. 3 "Early" EPCs appear within 4 to 7 days of culture, whereas "late" EPCs, also called endothe...
Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level. Areas covered: Pathogenic mutations in genes coding for the TGF-β receptors endoglin (ENG) (HHT1) or the activin receptor-like kinase-1 (ACVRL1 or ALK1) (HHT2), are responsible for more than 80% of patients with HHT. Therefore, ENG and ALK1 are the main potential therapeutic targets for HHT and the focus of this review. The current status of the preclinical and clinical studies, including the anti-angiogenic strategy, have been addressed. Expert opinion: Endoglin and ALK1 are attractive therapeutic targets in HHT. Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease.
SARS-CoV-2 viruses are positive single-stranded RNA viruses, whose infection can be asymptomatic or lead to the coronavirus disease 2019 . Covid-19 is a respiratory infection with a significant impact on the hematopoietic system and hemostasis leading to several cardiovascular complications. Hematologic consequences of this new infection allowed medical community to start new treatment approaches concerning infection going from targeted anti-inflammatory drugs to anticoagulation or stem cell therapies. A better understanding of Covid-19 pathophysiology, in particular hematological disorders, will help to choose appropriate treatment strategies.
The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or β1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng+/− mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-2099-4) contains supplementary material, which is available to authorized users.
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