Remodeling Of Vasculature Research Articles

Identification of novel genetic variants, including PIM1 and LINC01491, with ICD-10 based diagnosis of pulmonary arterial hypertension in the UK Biobank cohort.

Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary vasculature which results in elevations of pulmonary arterial pressures. Here, we conducted a genome-wide association study (GWAS) using the UK Biobank, analyzing the genomes of 493 individuals diagnosed with primary pulmonary hypertension, based on ICD-10 coding, compared to 24,650 age, sex, and ancestry-matched controls in a 1:50 case-control design. Genetic variants were analyzed by Plink's firth logistic regression and assessed for association with primary pulmonary hypertension. We identified three linked variants in the PIM1 gene, which encodes a protooncogene that has been garnering interest as a potential therapeutic target for PAH, that were associated with PAH with genome wide significance, one (rs192449585) of which lies in the promoter region of the gene. We also identified 15 linked variants in the LINC01491 gene. These results provide genetic evidence supporting the role of PIM1 inhibitors as a potential therapeutic option for PAH.

Transcription factors in the pathogenesis of pulmonary arterial hypertension-Current knowledge and therapeutic potential.

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure. Mortality remains high in severe cases despite significant advances in management and pharmacotherapy. Since currently approved PAH therapies are unable to significantly reverse pathological vessel remodeling, novel disease-modifying, targeted therapeutics are needed. Pathogenetically, PAH is characterized by vessel wall cell dysfunction with consecutive remodeling of the pulmonary vasculature and the right heart. Transcription factors (TFs) regulate the process of transcribing DNA into RNA and, in the pulmonary circulation, control the response of pulmonary vascular cells to macro- and microenvironmental stimuli. Often, TFs form complex protein interaction networks with other TFs or co-factors to allow for fine-tuning of gene expression. Therefore, identification of the underlying molecular mechanisms of TF (dys-)function is essential to develop tailored modulation strategies in PAH. This current review provides a compendium-style overview of TFs and TF complexes associated with PAH pathogenesis and highlights their potential as targets for vasculoregenerative or reverse remodeling therapies.

Prevalence and Risk Factors of Pulmonary Arterial Hypertension in Interstitial Lung Diseases: A Cross-sectional Study

Introduction: Interstitial Lung Diseases (ILD) is associated with inflammatory and/or fibrotic changes in the lungs. Pulmonary Arterial Hypertension (PAH) is a complication of many end-stage lung diseases due to the re-modelling of pulmonary vasculature associated with hypoxia leading to pulmonary vascular resistance. The Association of PAH in ILD contributes significantly to high morbidity and mortality. ILD being a progressive disease it is difficult to predict when the PAH will set in. Aim: To assess the clinical and radiological profiles of patients with ILD and to associate these with the severity of PAH. Materials and Methods: The present cross-sectional study was conducted in the Department of Respiratory Medicine at GSL Medical College on 23 patients with ILD from 1st October 2019 to 31st august 2021, in GSL medical college and hospital, Andhra Pradesh. Each patient was subjected to chest X-ray (CXR), Electrocardiogram (ECG), and 2-Dimensional Echocardiogram (2D ECHO). Evidence of PAH in any one investigation was considered. In ECG reports evidence of right ventricular enlargement (R>S in V1/V2 and right axis deviation >110 degrees, R=11 mm) was considered as PAH. CXR showing dilatation of the pulmonary artery with an increased cardiothoracic ratio was considered as PAH. A 2-D ECHO was performed to estimate the right arterial pressure and evidence of pulmonary arterial systemic pressure of >40 mmHg was considered as PAH. All the data were statistically analysed by using IBM Statistical Package for Social Sciences (SPSS) version 20.0. Results: Fifty-two percent of the population constituted females, and the mean age of the whole population was 59.7±14.4 years and the majority of them (65%) belonged to upper lower socioeconomic class. Usual Interstitial Pneumonia (UIP) was the most common pattern observed accounting for 57%. Prevalence of PAH was 65% and a longer duration of symptoms, 57% of the population had grade 3 of Modified Medical Research Council (MMRC) and 52.17% covered less than 200 meters in the 6-Minute Walk Test (6MWT). Oxygen desaturation after 6MWT was observed to be the contributing factor for the development of severe pulmonary hypertension in ILD patients. Conclusion: Factors like delayed seeking of medical care, co-morbidity like hypertension, higher grades of dyspnoea at the time of presentation, shorter 6MWD, and post-walk oxygen saturation were found to be predictors of pulmonary artery hypertension in patients with ILD. Early recognition of these risk factors in patients with ILD and the prompt treatment of the disease can reduce the development of severe PAH.

The Future of PAH Treatment

Pulmonary arterial hypertension (PAH) is a devastating disease mediated by vasoconstriction and vascular remodeling of the pulmonary vasculature. Current therapies target the imbalance of vasoconstrictors and vasorelaxants in 3 pathways: nitric oxide, prostacyclin, and endothelin. While these have extended lifespans for PAH patients, significant morbidity and mortality remains. Notably, the progress in PAH therapy for over a decade has utilized these same 3 pathways. Fortunately, several new treatment options utilizing different mechanisms are emerging and will be reviewed here.

Abstract B002: A facilitating role for semaphorin-7a in regulating cell invasion and matrix remodeling for DCIS progression

Abstract Approximately 25% of newly diagnosed breast cancer cases are non-invasive or pre-invasive breast cancers known as ductal carcinoma in situ (DCIS). DCIS can progress to invasive ductal carcinoma (IDC), conferring a more dangerous prognosis; however, there is a gap in knowledge regarding what ultimately causes this transition. Understanding epithelial invasion in the mammary gland will provide insight on how DCIS ultimately progresses to IDC. Our lab has found that DCIS transforms to IDC under the “wound-healing” pressure of postpartum tissue remodeling – termed postpartum mammary gland involution. This invasive transformation is dependent, in part, on collagen-induced cyclooxygenase (COX2) expression. We identified that a membrane-bound signaling molecule, semaphorin-7a (SEMA7A), promotes both collagen deposition and COX-2 expression and therefore DCIS progression. SEMA7A is also naturally upregulated in mammary epithelial cells during postpartum involution and in DCIS relative to normal epithelium. We have identified that inhibition or silencing of SEMA7A can inhibit DCIS invasion. While this demonstrates that SEMA7A expression is sufficient to promote innate capacity for tumor cell invasiveness, we have yet to investigate how SEMA7A interacts with the tumor microenvironment (TME) to promote stromal changes known to advance this transition, such as collagen remodeling or immune cell recruitment. We have demonstrated a potential role for DCIS-associated macrophages in facilitating this transition. Additionally, we have found that SEMA7A polarizes macrophages to an M2-like state, and this promotes remodeling of the lymphatic vasculature as well as tumor cell entry into lymphatic vessels. Furthermore, we have shown that SEMA7A promotes expression of matrix remodeling enzymes that can, in turn, promote shedding of SEMA7A into the TME where it can affect other cell types. We are utilizing intravital imaging to visualize tumor/lymphatic/macrophage interactions as well as second harmonic imaging to visualize SEMA7A-dependent changes in the collagen structure surrounding DCIS lesions. Our results suggest that SEMA7A mediates DCIS invasion through both intrinsic and extrinsic mechanisms, which could facilitate progression to metastasis. By understanding how SEMA7A regulates DCIS progression we can begin to introduce potential targets for preventative therapies for development of invasive disease – including targeting SEMA7A itself. Since SEMA7A is low in most adult tissues it is expected that such a therapeutic would be less toxic for patients than the current prescribed therapies. Citation Format: Petra Dahms. A facilitating role for semaphorin-7a in regulating cell invasion and matrix remodeling for DCIS progression [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B002.

The multifaceted role of GCM1 during trophoblast differentiation in the human placenta

Remodeling of the uterine vasculature by invasive extravillous trophoblasts (EVTs) is a critical aspect of human placentation. Insufficient EVT invasion can lead to severe obstetrical complications like preeclampsia, intrauterine growth restriction, and preterm birth. Glial cells missing-1 (GCM1) is a transcription factor that is crucial for proper placentation in mice, and is highly expressed in human syncytiotrophoblast (ST) and EVTs. GCM1 is classically considered a master regulator of ST formation, but little is known about its contribution to the development and function of EVTs. Therefore, in this study we test the hypothesis that GCM1 is a critical regulator of both EVT and ST development and function. We show that GCM1 is highly expressed in human trophoblast stem (TS) cells differentiated into either ST or EVTs. Knockdown of GCM1 in TS cells hindered differentiation into both ST and EVT pathways. When placed in ST media, GCM1-knockdown cells formed small, unstable clusters; when placed in EVT media, cells had altered morphology and transcript profiles resembling cells trapped in an intermediate state between CT and EVT, and invasive capacity through matrix was reduced. RNA sequencing analysis of GCM1-deficient TS cells revealed downregulation of EVT-associated genes and enrichment in transcripts related to WNT signaling, which was linked to decreased expression of the EVT master regulator ASCL2 and the WNT antagonist NOTUM. Our findings reveal an essential role of GCM1 during ST and EVT development, and suggest that GCM1 regulates differentiation of human TS cells into EVTs by inducing expression of ASCL2 and NOTUM.

Abstract 10487: In vivo Efficacy of HS135, a Novel Activin and GDF Trap for the Treatment of Pulmonary Hypertension (PH) and Metabolic Syndrome (MetS)

Introduction: PH is a disorder characterized by remodeling of the pulmonary vasculature which causes increased pulmonary vascular resistance and ultimately right ventricular (RV) failure leading to death. MetS is a recognized risk factor for PH, particularly in patients suffering from PH associated with left-sided heart failure (WHO Group 2 PH) for which there are no approved therapies. Activins and growth differentiation factors (GDFs) are implicated in both PH pathology as well as body composition and metabolism by genetic disease association, preclinical, translational, and clinical evidence. HS135 is a rationally designed first-in-class activin-receptor (ActR)-based fusion protein that addresses both vascular remodeling and MetS in PH without affecting hematological parameters; hematological effects limit the dosing of other ActR-based agents. Methods: HS135’s ability to counteract vascular remodeling and heart failure in PH was assessed using a rat monocrotaline (MCT) model: a single dose of 60 mg/kg MCT was administered on Day 0 followed by 4 weeks of twice weekly treatment with either HS135 (1, 4, or 16 mg/kg) or vehicle. PH efficacy was assessed at end of study by echocardiography and histological readouts. HS135’s ability to improve body composition and metabolism was assessed in wild type mice by administering HS135 (1, 3, 10, 20, or 50 mg/kg) or vehicle twice weekly for 3 weeks. The effect of HS135 on hematological parameters was assessed by whole blood cell count in non-human primates (NHPs) 2 weeks following a single administration of HS135 at 3 or 30 mg/kg. Results: HS135 at 3 or 30 mg/kg did not lead to changes in hematological parameters in NHPs. Compared to vehicle, HS135 was effective at counteracting the MCT-induced PH phenotype in rats as evidenced by significant reductions in Fulton index and improved echocardiography parameters. In wild type mice, HS135 led to significant improvements in body composition. Conclusions: Contrary to other ActR-based therapies, HS135 did not lead to increases in hematocrit which would limit its dosing. HS135 was efficacious at treating PH while simultaneously improving body composition in preclinical models. Clinical trials with HS135 are expected to commence within 2023.

Impact of Rapid Weight Loss after Bariatric Surgery in Systemic Inflammatory Response and Pulmonary Hemodynamics in Severely Obese Subjects with Pulmonary Hypertension.

Pulmonary hypertension (PH) can be associated with obesity. The excessive production of proinflammatory mediators by dysfunctional adipocytes may enhance remodeling of the pulmonary vasculature and worsen pulmonary hemodynamics. This study aimed to describe the changes in pulmonary arterial pressures and systemic inflammation in patients with obesity with PH after bariatric surgery (BaS). In this retrospective cohort study, we compared patients with PH who underwent BaS from 2008 to 2018 at our institution (group 1) to a group of severely obese patients with PH (group 2). Echocardiographic right ventricular systolic pressure (RVSP) was used as an indirect measurement of pulmonary arterial pressures. Red blood cell distribution width (RDW) was used as a marker of systemic inflammation. A total of 40 patients were included, 20 per group. In group 1, the RVSP decreased from 44.69 ± 7.12 mmHg to 38.73 ± 12.81 mmHg (p = 0.041), and the RDW decreased from 15.22 ± 1.53 to 14.41 ± 1.31 (p = 0.020). In group 2, the RVSP decreased from 60.14 ± 18.08 to 59.15 ± 19.10 (0.828), and the RDW increased from 15.37 ± 1.99 to 15.38 ± 1.26 (0.983). For both groups, we found a positive correlation between RVSP and RDW changes, although the correlation was not statistically significant. Previous studies suggest BaS could be a safe and effective procedure to achieve weight loss in obese patients with PH, with an additional modest improvement in pulmonary hemodynamics. The results of this study reinforce this observation and suggest that such improvement could be related to a decrease in systemic inflammation. Further prospective studies with bigger samples are needed to better understand these findings.

Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema.

Lymphedema (LD) refers to a condition of lymphatic dysfunction associated with excessive fluid accumulation, fibroadipose tissue deposition and swelling. In industrialized countries, LD development mainly results from a local disruption of the lymphatic network by an infection or cancer-related surgery (secondary LD). In the absence of efficient therapy, animal models are needed to decipher the cellular and molecular mechanisms underlying LD and test putative drugs. In this study, we optimized and characterized a murine model of LD that combines an irradiation of the mice hind limb and a radical surgery (lymph node resection associated to lymphatic vessel ligation). We investigated the respective roles of irradiation and surgery in LD formation by comparing their impacts, alone or in combination (with different intervention sequences), on eight different features of the pathology: swelling (paw thickness), indocyanine green (ICG) clearance, lymphatic vasculature remodeling, epidermal and dermal thickening, adipocyte accumulation, inflammatory cell infiltration and collagen deposition. This study supports the importance of radiation prior to surgery to experimentally induce a rapid, severe and sustained tissue remodeling harboring the different hallmarks of LD. We provide the first experimental evidence for an excessive deposition of periostin (POSTN) and tenascin-C (TNC) in LD. Through a computerized method of digital image quantification, we established the spatial map of lymphatic expansion, as well as collagen, POSTN and TNC deposition in papillary and reticular dermis of lymphedematous skins. This mouse model is available to study the patho-physiology of LD and test potential therapeutic targets.

Efficacy and safety of selexipag in real-life in patients with pulmonary arterial hypertension: early results of RAMPHA study

Abstract Background Pulmonary arterial hypertension (PAH) is a syndrome characterized by marked remodeling of the pulmonary vasculature and leading to right heart failure and death. Selexipag, an oral prostacyclin IP receptor agonist, has been shown to decrease morbidity and mortality compared to patients treated with placebo. Purpose Our aim was to evaluate the efficacy and safety of Selexipag in patients with PAH in real-life. Methods The RAMPHA study was a multicenter, observational and retrospective trial of patients who had PAH and began taking Selexipag between 2017–2021. We analyzed baseline characteristics, risk profiles, clinical assessments that were used for risk stratification and events in follow-up time. Results 29 patients aged 48±14 were initially studied. 23 (79%) were women. Within the pulmonary hypertension-classification, 10 (34,5%) had PAH associated-congenital heart disease, 9 (31%) had idiopathic HAP, 7 (24,1%) had PAH associated with connective tissue disease, 1 had PAH associated to HIV and 2 heritable PAH. The time from PAH diagnoses to the beginning of Selexipag treatment was 54 months (IQR 89). 89,7% (26) were in treatment with doubled combination therapy with PDE5i+ARE; Sildenafil was the most widely used PDE5i and bosentan (37,9%) the most used ARE. No patients were under treatment with intravenous prostacyclin analogue, but 3 were with Treprostinil (1 of them subcutaneous and 2 inhaled) and 2 patients with iloprost. Most patients were categorized in intermediate risk profile (figure 1), using the risk stratification strategy of ESC/ERS PH guidelines. In the approach of risk assessment before start with Selexipag, clinical, functional, exercise (with 6MWT) and echocardiographic variables were used in all the patients. Biochemical variables with NT-proBNP were used in 93% of the patients. Only 15 patients had a right catheterization to get haemodynamic parameters before the treatment. At follow up, 11 patients (38%) improved functional class, only 1 patient got worst (p=0,001). 3 patients improved risk-profile in the exercise test and, in the others, a quantitative improvement was found. NT-proBNP levels were not significant better (924ng/l IQR 1209 vs 760ng/l IQR 1397). There were not changes in RV function in the echocardiographic parameters. Selexipag was well-tolerated, 86% of the patients experienced side effects, but none had to discountinue the treatment. The most common side effect was headache. The titration lasted 68 days (IQR 72) and 38% of the patients got maximum doses. At the medium-term follow-up of 52 months, the free-event survival (worsening of PAH that resulted in hospitalization; initiation of parenteral prostanoid therapy or death to PAH; or any cause) was 80% (Figure 2). Conclusion Selexipag, added as triple combination therapy in patients with PAH intermediate risk, improved risk variables, was well tolerated and achieved a medium-long-term free-event survival greater than 80%. Funding Acknowledgement Type of funding sources: None.

AMIODARONE THYROTOXICOSIS LEADING TO PULMONARY HYPERTENSION

AMIODARONE THYROTOXICOSIS LEADING TO PULMONARY HYPERTENSION

A CASE OF PULMONARY TUMOR THROMBOEMBOLIC MICROANGIOPATHY FROM PROSTATE CARCINOMA

A CASE OF PULMONARY TUMOR THROMBOEMBOLIC MICROANGIOPATHY FROM PROSTATE CARCINOMA

Agenesis of the ICA with a Contralateral Cavernous-Supraclinoid Anastomotic Vessel

Congenital agenesis of an ICA is exceptionally rare. Survival requires remodeling of the intracranial vasculature, with several classic vascular patterns and anastomoses having been recognized in the literature. We present a patient with ICA agenesis who exhibited a distinctive anastomotic vessel extending from the contralateral cavernous carotid artery directly to the supraclinoid ICA on the affected side, a finding only documented in a handful of patients with this already rare condition.

MiR-210-3p protects against osteoarthritis through inhibiting subchondral angiogenesis by targeting the expression of TGFBR1 and ID4.

Excessive subchondral angiogenesis is a key pathological feature of osteoarthritis (OA), as it alters the balance of subchondral bone remodeling and causes progressive cartilage degradation. We previously found that miR-210-3p correlates negatively with angiogenesis, though the specific mechanism of miR-210-3p-related angiogenesis in subchondral bone during OA progression remains unclear. This study was conducted to identify the miR-210-3p-modulating subchondral angiogenesis mechanism in OA and investigate its therapeutic effect. We found that miR-210-3p expression correlated negatively with subchondral endomucin positive (Emcn+) vasculature in the knee joints of OA mice. miR-210-3p overexpression regulated the angiogenic ability of endothelial cells (ECs) under hypoxic conditions in vitro. Mechanistically, miR-210-3p inhibited ECs angiogenesis by suppressing transforming growth factor beta receptor 1 (TGFBR1) mRNA translation and degrading DNA-binding inhibitor 4 (ID4) mRNA. In addition, TGFBR1 downregulated the expression of ID4. Reduced ID4 levels led to a negative feedback regulation of TGFBR1, enhancing the inhibitory effect of miR-210-3p on angiogenesis. In OA mice, miR-210-3p overexpression in ECs via adeno-associated virus (AAV) alleviated cartilage degradation, suppressed the type 17 immune response and relieved symptoms by attenuating subchondral Emcn+ vasculature and subchondral bone remodeling. In conclusion, we identified a miR-210-3p/TGFBR1/ID4 axis in subchondral ECs that modulates OA progression via subchondral angiogenesis, representing a potential OA therapy target.

Apolipoprotein A5 ameliorates MCT induced pulmonary hypertension by inhibiting ER stress in a GRP78 dependent mechanism

BackgroundPulmonary arterial hypertension (PAH) is a chronic, progressive lung vascular disease accompanied by elevated pulmonary vascular pressure and resistance, and it is characterized by increased pulmonary artery smooth muscle cell (PASMC) proliferation. Apolipoprotein A5 (ApoA5) improves monocrotaline (MCT)-induced PAH and right heart failure; however, the underlying mechanism remains unknown. Here we speculate that ApoA5 has a protective effect in pulmonary vessels and aim to evaluate the mechanism.MethodsApoA5 is overexpressed in an MCT-induced PAH animal model and platelet-derived growth factor (PDGF)-BB-induced proliferating PASMCs. Lung vasculature remodeling was measured by immunostaining, and PASMC proliferation was determined by cell counting kit‐8 and 5‐ethynyl‐2'‐deoxyuridine5‐ethynyl‐2'‐deoxyuridine incorporation assays. Coimmunoprecipitation-mass spectrometry was used to investigate the probable mechanism. Next, its role and mechanism were further verified by knockdown studies.ResultsApoA5 level was decreased in MCT-induced PAH lung as well as PASMCs. Overexpression of ApoA5 could help to inhibit the remodeling of pulmonary artery smooth muscle. ApoA5 could inhibit PDGF-BB-induced PASMC proliferation and endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78 (GRP78). After knocking down GRP78, the protecting effects of ApoA5 have been blocked.ConclusionApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism.

Radiation-induced cardiac side-effects: The lung as target for interacting damage and intervention.

Radiotherapy is part of the treatment for many thoracic cancers. During this treatment heart and lung tissue can often receive considerable doses of radiation. Doses to the heart can potentially lead to cardiac effects such as pericarditis and myocardial fibrosis. Common side effects after lung irradiation are pneumonitis and pulmonary fibrosis. It has also been shown that lung irradiation has effects on cardiac function. In a rat model lung irradiation caused remodeling of the pulmonary vasculature increasing resistance of the pulmonary vascular bed, leading to enhanced pulmonary artery pressure, right ventricle hypertrophy and reduced right ventricle performance. Even more pronounced effects are observed when both, lung and heart are irradiated.The effects observed after lung irradiation show striking similarities with symptoms of pulmonary arterial hypertension. In particular, the vascular remodeling in lung tissue seems to have similar underlying features. Here, we discuss the similarities and differences of vascular remodeling observed after thoracic irradiation compared to those in pulmonary arterial hypertension patients and research models. We will also assess how this knowledge of similarities could potentially be translated into interventions which would be beneficial for patients treated for thoracic tumors, where dose to lung tissue is often unavoidable.

Potential role of cellular senescence in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare and chronic lung vasculature disease characterised by pulmonary vasculature remodelling, including abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional endothelial cells (ECs). Remodelling of the pulmonary vasculature occurs from maturity to senescence, and it has become apparent that cellular senescence plays a central role in the pathogenesis of various degenerative vascular diseases and pulmonary pathologies. Cellular senescence represents a state of stable proliferative arrest accompanied by the senescence-associated secretory phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment. Evidence shows that in PAH patients, higher levels of cytokines, chemokines and inflammatory mediators can be detected and correlate with clinical outcome. Moreover, senescent cells accrue with age in epithelial, endothelial, fibroblastic and immunological compartments within human lungs, and evidence has shown that ECs and PASMCs in lungs from patients with chronic obstructive pulmonary disease were characterised by a higher number of senescent cells. However, there is little evidence uncovering the molecular pulmonary vasculature senescence in PAH. Herein, we review the cellular senescence in pulmonary vascular remodelling, and emphasise its importance in PAH. We further introduce some signalling pathways which might be involved in vasculature senescence and PAH, with the intent to discuss the possibility of the PAH therapy via targeting cellular senescence and reduce PAH progression and mortality.

Hypoplastic Left Heart Syndrome: Is There a Role for Fetal Therapy?

During fetal life some cardiac defects may lead to diminished left heart growth and to the evolution of a form of hypoplastic left heart syndrome (HLHS). In fetuses with an established HLHS, severe restriction or premature closure of the atrial septum leads to left atrial hypertension and remodeling of the pulmonary vasculature, severely worsening an already poor prognosis. Fetal therapy, including invasive fetal cardiac interventions and non-invasive maternal hyperoxygenation, have been introduced to prevent a possible progression of left heart hypoplasia, improve postnatal outcome, or secure fetal survival. The aim of this review is to cover patient selection and possible hemodynamic effects of fetal cardiac procedures and maternal hyperoxygenation in fetuses with an evolving or established hypoplastic left heart syndrome.

Vascular Remodeling Is a Crucial Event in the Early Phase of Hepatocarcinogenesis in Rodent Models for Liver Tumorigenesis.

Simple SummaryHepatocellular carcinoma (HCC) is a highly vascularized tumor and remodeling of the tumor vasculature is one of the hallmarks of tumor progression. Mouse models are elegant tools to study the onset and progression of liver tumors. However, only few data exist on the vasculature and vascular remodeling processes especially in the early phase of hepatocarcinogenesis. The aim of this study was therefore to perform a comprehensive characterization and comparison of the vasculature in mouse models used for hepatocarcinogenesis studies. For this purpose, we characterized the preneoplastic foci of cellular alteration (FCA) and hepatocellular carcinoma (HCC) by using tissue-based techniques and computer-assisted analysis to better understand if and how vascular remodeling appears in rodent models for liver tumorigenesis. Our findings demonstrated crucial differences in the number and size of the vessels, degree of maturation and intratumoral localization of the vasculature in FCA and HCC, clearly indicating that vascular remodeling is an important step in the early phase of liver tumorigenesis of rodent models.The investigation of hepatocarcinogenesis is a major field of interest in oncology research and rodent models are commonly used to unravel the pathophysiology of onset and progression of hepatocellular carcinoma. HCC is a highly vascularized tumor and vascular remodeling is one of the hallmarks of tumor progression. To date, only a few detailed data exist about the vasculature and vascular remodeling in rodent models used for hepatocarcinogenesis. In this study, the vasculature of HCC and the preneoplastic foci of alteration (FCA) of different mouse models with varying genetic backgrounds were comprehensively characterized by using immunohistochemistry (CD31, Collagen IV, αSMA, Desmin and LYVE1) and RNA in situ hybridization (VEGF-A). Computational image analysis was performed to evaluate selected parameters including microvessel density, pericyte coverage, vessel size, intratumoral vessel distribution and architecture using the Aperio ImageScope and Definiens software programs. HCC presented with a significantly lower number of vessels, but larger vessel size and increased coverage, leading to a higher degree of maturation, whereas FCA lesions presented with a higher microvessel density and a higher amount of smaller but more immature vessels. Our results clearly demonstrate that vascular remodeling is present and crucial in early stages of experimental hepatocarcinogenesis. In addition, our detailed characterization provides a strong basis for further angiogenesis studies in these experimental models.

Comprehensive characterization of the prostate tumor microenvironment identifies CXCR4/CXCL12 crosstalk as a novel antiangiogenic therapeutic target in prostate cancer

BackgroundCrosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME.MethodsTEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell–cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model.ResultsCompared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro.ConclusionsOverall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa.Graphical