Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2.
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ABSTRACT:
SUBMITTER: Zhao G
PROVIDER: S-EPMC7688336 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Comprehensive understanding of the mechanisms regulating angiogenesis might provide new strategies for angiogenic therapies for treating diverse physiological and pathological ischemic conditions. The E-twenty six (ETS) factor Ets variant 2 (ETV2; aka Ets-related protein 71) is essential for the formation of hematopoietic and vascular systems. Despite its indispensable function in vessel development, ETV2 role in adult angiogenesis has not yet been addressed. We have therefore investigated the role of ETV2 in vascular regeneration.We used endothelial Etv2 conditional knockout mice and ischemic injury models to assess the role of ETV2 in vascular regeneration. Although Etv2 expression was not detectable under steady-state conditions, its expression was readily observed in endothelial cells after injury. Mice lacking endothelial Etv2 displayed impaired neovascularization in response to eye injury, wounding, or hindlimb ischemic injury. Lentiviral Etv2 expression in ischemic hindlimbs led to improved recovery of blood perfusion with enhanced vessel formation. After injury, fetal liver kinase 1 (Flk1), aka VEGFR2, expression and neovascularization were significantly upregulated by Etv2, whereas Flk1 expression and vascular endothelial growth factor response were significantly blunted in Etv2-deficient endothelial cells. Conversely, enforced Etv2 expression enhanced vascular endothelial growth factor-mediated endothelial sprouting from embryoid bodies. Lentiviral Flk1 expression rescued angiogenesis defects in endothelial Etv2 conditional knockout mice after hindlimb ischemic injury. Furthermore, Etv2(+/-); Flk1(+/-) double heterozygous mice displayed a more severe hindlimb ischemic injury response compared with Etv2(+/-) or Flk1(+/-) heterozygous mice, revealing an epistatic interaction between ETV2 and FLK1 in vascular regeneration.Our study demonstrates a novel obligatory role for the ETV2 in postnatal vascular repair and regeneration.
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Project description:PurposeTo investigate pulmonary vascular abnormalities at CT pulmonary angiography (CT-PE) in patients with coronavirus disease 2019 (COVID-19) pneumonia.Materials and methodsIn this retrospective study, 48 patients with reverse-transcription polymerase chain reaction-confirmed COVID-19 infection who had undergone CT-PE between March 23 and April 6, 2020, in a large urban health care system were included. Patient demographics and clinical data were collected through the electronic medical record system. Twenty-five patients underwent dual-energy CT (DECT) as part of the standard CT-PE protocol at a subset of the hospitals. Two thoracic radiologists independently assessed all studies. Disagreement in assessment was resolved by consensus discussion with a third thoracic radiologist.ResultsOf the 48 patients, 45 patients required admission, with 18 admitted to the intensive care unit, and 13 requiring intubation. Seven patients (15%) were found to have pulmonary emboli. Dilated vessels were seen in 41 cases (85%), with 38 (78%) and 27 (55%) cases demonstrating vessel enlargement within and outside of lung opacities, respectively. Dilated distal vessels extending to the pleura and fissures were seen in 40 cases (82%) and 30 cases (61%), respectively. At DECT, mosaic perfusion pattern was observed in 24 cases (96%), regional hyperemia overlapping with areas of pulmonary opacities or immediately surrounding the opacities were seen in 13 cases (52%), opacities associated with corresponding oligemia were seen in 24 cases (96%), and hyperemic halo was seen in 9 cases (36%).ConclusionPulmonary vascular abnormalities such as vessel enlargement and regional mosaic perfusion patterns are common in COVID-19 pneumonia. Perfusion abnormalities are also frequently observed at DECT in COVID-19 pneumonia and may suggest an underlying vascular process.Supplemental material is available for this article.© RSNA, 2020.
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Project description:ObjectivesDuring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, dramatic endothelial cell damage with pulmonary microvascular thrombosis have been was hypothesized to occur. The aim was to assess whether pulmonary vascular thrombosis (PVT) is due to recurrent thromboembolism from peripheral deep vein thrombosis or to local inflammatory endothelial damage, with a superimposed thrombotic late complication.DesignObservational study.SettingMedical and intensive care unit wards of a teaching hospital.ParticipantsThe authors report a subset of patients included in a prospective institutional study (CovidBiob study) with clinical suspicion of pulmonary vascular thromboembolism.InterventionsComputed tomography pulmonary angiography and evaluation of laboratory markers and coagulation profile.Measurements and main resultsTwenty-eight of 55 (50.9%) patients showed PVT, with a median time interval from symptom onset of 17.5 days. Simultaneous multiple PVTs were identified in 22 patients, with bilateral involvement in 16, mostly affecting segmental/subsegmental pulmonary artery branches (67.8% and 96.4%). Patients with PVT had significantly higher ground glass opacity areas (31.7% [22.9-41] v 17.8% [10.8-22.1], p < 0.001) compared with those without PVT. Remarkably, in all 28 patients, ground glass opacities areas and PVT had an almost perfect spatial overlap. D-dimer level at hospital admission was predictive of PVT.ConclusionsThe findings identified a specific radiologic pattern of coronavirus disease 2019 (COVID-19) pneumonia with a unique spatial distribution of PVT overlapping areas of ground-glass opacities. These findings supported the hypothesis of a pathogenetic relationship between COVID-19 lung inflammation and PVT and challenged the previous definition of pulmonary embolism associated with COVID-19 pneumonia.
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Project description:BackgroundPulmonary manifestations of COVID-19 pneumonia are well known. However, COVID-19 is also associated with a range of vascular manifestations such as embolism, congestion, and perfusion changes. Regarding congestion, research from different groups has suggested arteriovenous anastomosis dysregulation as a contributing factor. In this study, we aim to better describe the changes in vascular volume in affected lung zones and to relate them to pathophysiological hypotheses.MethodsWe performed automatic vascular volume extraction in 10 chest CTs of patients, including 2 female and 8 male with a mean age of 63.5 ± 9.3 years, diagnosed with COVID-19 pneumonia. We compared the proportion of vascular volumes between manually segmented regions of lung parenchyma with and without signs of pneumonia.ResultsThe proportion of vascular volume was significantly higher in COVID (CVasc) compared to non-COVID (NCVasc) areas. We found a mean difference (DVasc) of 5% and a mean ratio (RVasc) of 3.7 between the two compartments (p < 0.01).ConclusionVascular volume in COVID-19 affected lung parenchyma is augmented relative to normal lung parenchyma, indicating venous congestion and supporting the hypothesis of pre-existing intra-pulmonary arteriovenous shunts.
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Project description:The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in Mgp-null lungs. Elevated HGF induced hepatocyte nuclear factor 4 ? (Hnf4a), which competed with NK2 homeobox 1 (Nkx2.1) for binding to forkhead box A2 (Foxa2) to drive hepatic differentiation in Mgp-null airway progenitor cells. Limiting endothelial HGF reduced Hnf4a, abolished interference of Hnf4a with Foxa2, and reduced hepatic differentiation in Mgp-null lungs. Together, our results suggest that endothelial-epithelial interactions, maintained by MGP, are essential in pulmonary cell differentiation.
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Project description:Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs?75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs?77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.
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