Velcrin molecular glues induce apoptosis in glioblastomas with high PDE3A and SLFN12 expression.

Background: Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines. We therefore aim to characterize velcrins as novel therapeutic agents in glioblastoma. Materials and Methods: PDE3A and SLFN12 expression levels were measured in glioblastoma cell lines, the Cancer Genome Atlas (TCGA) tumor samples, and tumor neurospheres. Velcrin-treated cells were assayed for viability, induction of apoptosis, cell cycle phases, and global changes in translation. Transcriptional profiling of the cells was obtained. Xenograft-harboring mice treated with velcrins were also monitored for survival. Results: We identified several velcrin-sensitive glioblastoma cell lines and 4 velcrin-sensitive glioblastoma patient-derived models. We determined that BAY 2666605 crosses the blood-brain barrier and elicits full tumor regression in an orthotopic xenograft model of GB1 cells. We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models. Conclusions: Velcrins have antitumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.

Intramyocardial immunomodulation with human CD16+ monocytes to treat myocardial infarction in pig: a blind randomized preclinical trial.

Background: Human CD16+ monocytes (hCD16+ Ms) have proangiogenic properties. We assessed the feasibility, safety and efficacy of hCD16+ Ms in a porcine model of myocardial infarction (MI). Methods and results: A total of 27 female Large White pigs underwent MI with reperfusion and cardiac magnetic resonance (CMR). Five days later, animals received intramyocardial injections of hCD16+ Ms in saline (n = 13) or saline only (n = 14). hCD16+ Ms were selected from leucocyte cones. Feasibility/safety endpoints included injury at injected sites, malignant arrhythmias, cancer, haematoma, left ventricular (LV) dilatation, troponin release and downstream organ injury. Co-primary efficacy outcome included LV scar and ejection fraction (LVEF) at 30-day post-injections by CMR. Immunohistochemistry included neo-angiogenesis, fibrosis, markers of myofibroblast and inflammation. Four animals were excluded before injections due to untreatable malignant arrhythmias or lung injury. Median cell number and viability were 48.75 million and 87%, respectively. No feasibility/safety concerns were associated with the use of hCD16+ Ms. The LV scar dropped by 14.5gr (from 25.45 ± 8.24 to 10.8 ± 3.4 gr; -55%) and 6.4gr (from 18.83 ± 5.06 to 12.4 ± 3.9gr; -30%) in the hCD16+ Ms and control groups, respectively (p = 0.015). The 30-day LVEF did not differ between groups, but a prespecified sub-analysis within the hCD16+ Ms group showed that LVEF was 2.8% higher and LV scar 1.9gr lower in the subgroup receiving a higher cell dose. Higher tissue levels of neo-angiogenesis, myofibroblast and IL-6 and lower levels of TGF-ß were observed in the hCD16+ Ms group. Conclusions: The use of hCD16+ Ms in acute MI is feasible, safe and associated with reduced LV scar size, increased tissue levels of neo-angiogenesis, myofibroblasts and IL-6 and reduced pro-fibrotic TGF-ß at 30-day post-injections. A higher cell dose might increase the LVEF effect while reducing scar size, but this warrants validation in future studies.

An analysis of risk factors for child suicide in three centres from 2008 to 2017.

As a part of a study of suicide in children aged 17 years and under in three centers-Hennepin County in the United States (US), Auckland in New Zealand (NZ), and South Australia in Australia (AUS) from 2008 to 2017 it was decided to characterize potential risk factors and to determine whether these differed by jurisdiction. Reviewed data included a history of psychiatric illness, symptoms prior to suicide, events preceding suicide, previous suicidal ideation or suicide attempts, and communication of suicidal intent. The most common events preceding suicide were arguments with family/friends and relationship issues; in addition depression with or without expressed suicidal ideation, self-harming behavior, sadness, distress, drug/substance abuse, and anorexia were documented. Suicidal intent was on occasion communicated via technological means. In 79.5% of cases in South Australia decedents had a previously diagnosed psychiatric illness, with 62% in Hennepin County. This compared to a much lower proportion of cases in Auckland (23.8%). Whether this reflects more limited access to psychiatric services or a reluctance to seek support and therapy in Auckland is unclear. It does, however, demonstrate that risk factors for child suicide are not uniform among communities and so extrapolation of data from one area to another may not be appropriate. Disturbingly parents/carers were not aware of the decedent's suicidal intent in 84-87.2% of cases.

Vicariant speciation resulting from biogeographic barriers in the Australian tropics: The case of the red-cheeked dunnart (Sminthopsis virginiae).

Global biodiversity loss continues unabated, and in Australia, the rate of recent mammal extinctions is among the worst in the world. Meanwhile, the diversity among and within many endemic mammal species remains undescribed. This information is crucial to delineate species boundaries and thus inform decision-making for conservation. Sminthopsis virginiae (the red-cheeked dunnart) is a small, dasyurid marsupial found in four disjunct populations around the northern coast of Australia and New Guinea. There are three currently recognized subspecies, each occupying a distinct geographic location. Sminthopsis v. virginiae occurs in Queensland, S. v. rufigenis is distributed across New Guinea and the Aru Islands, and S. v. nitela has populations in the Top End of the Northern Territory and the Kimberley region of Western Australia. Previous molecular work has suggested the current subspecies definitions are not aligned with DNA sequence data, though the sampling was limited. We undertook a comprehensive genetic and morphological review of S. virginiae to clarify relationships within the species. This included mitochondrial (CR, 12S, and cytb) and nuclear (omega-globin, IRBP, and bfib7) loci, and morphometric analysis of skulls and whole wet-preserved specimens held in museums. Maximum Likelihood and Bayesian phylogenetic analyses resolved samples into two distinct clades, demarcated by the Gulf of Carpentaria in Australia's north. Sminthopsis. v. nitela was consistently separated from S. v. virginiae and S. v. rufigenis, based on the overall body and skull size and craniodental features, while S. v. virginiae and S. v. rufigenis were more difficult to distinguish from each other. Thus, we redescribed S. virginiae, recognizing two species, S. nitela (raised from subspecies) and S. virginiae (now comprising the subspecies S. v. virginiae and S. v. rufigenis). This study highlights the importance of recognizing cryptic mammal fauna to help address the gap in our knowledge about diagnosing diversity during a time of conservation crisis.

Density of a cryptic Australian small mammal: The threatened Julia Creek dunnart (Sminthopsis douglasi).

Globally, hundreds of mammal species face the threat of extinction in the coming decades, and in many cases, their ecology remains poorly understood. Fundamental ecological knowledge is crucial for effective conservation management of these species, but it is particularly lacking for small, cryptic mammals. The Julia Creek dunnart (Sminthopsis douglasi), a threatened, cryptic carnivorous marsupial that occurs in scattered populations in the central west of Queensland, Australia, was once so poorly studied that it was believed extinct. Sporadic research since its rediscovery in the early 1990s has revealed that S. douglasi is distributed across land at risk from many threats. Fundamental knowledge of S. douglasi population density is urgently required to inform conservation management at key sites, yet the species has historically proven hard to detect. Indeed, the status of the largest known population of S. douglasi, in Bladensburg National Park, is unknown. Here, we conducted a population study on S. douglasi at two sites within Bladensburg National Park via live mark-recapture surveys during 2022 and 2023. From likelihood-based spatially explicit capture-recapture (SECR) modelling we provide the first estimates of density and population size for S. douglasi. Live trapping resulted in captures of 49 individual S. douglasi (with 83 captures total, including recaptures). We estimated S. douglasi to occur at a density of 0.38 individuals ha-1 (0.25-0.58) at one site and 0.16 individuals ha-1 (0.09-0.27) at another site, with an estimated mean population size in suitable habitat at Bladensburg National Park of 1211 individuals (776-1646). Our S. douglasi density estimates were similar to that reported for other threatened small mammals in Australia. We also found evidence of extreme S. douglasi population fluctuations over time at Bladensburg National Park, which is of concern for its future conservation. Our study has provided the first estimate of density for S. douglasi, a threatened dasyurid species from the Mitchell Grass Downs of central western Queensland, Australia. Our research provides crucial population data to assist the management of this poorly studied species. We demonstrate a method that can be applied to species with low detection probability to ultimately help address the mammal extinction crisis faced by Australia and the rest of the world.

Inhibition of endothelial to mesenchymal transition in a large animal preclinical arterio-venous fistula model leads to improved remodeling and reduced stenosis.

AIMS: Vein grafts are used for many indications, including bypass graft surgery and arterio-venous fistula (AVF) formation. However, patency following vein grafting or AVF formation is suboptimal for various reasons, including thrombosis, neointimal hyperplasia and adverse remodeling. Recently, endothelial to mesenchymal transition (EndMT) was found to contribute to neointimal hyperplasia in mouse vein grafts. We aimed to evaluate the clinical potential of inhibiting EndMT, and developed the first dedicated preclinical model to study the efficacy of local EndMT inhibition immediately prior to AVF creation. METHODS AND RESULTS: We first undertook pilot studies to optimize the creation of a femoral AVF in pigs and verify that EndMT contributes to neointimal formation. We then developed a method to achieve local in vivo SMAD3 knockdown by dwelling a lentiviral construct containing SMAD3 shRNA in the femoral vein prior to AVF creation. Next, in Phase 1, 6 pigs were randomized to SMAD3 knockdown or control lentivirus to evaluate the effectiveness of SMAD3 knockdown and EndMT inhibition 8 days after AVF creation. In Phase 2, 16 pigs were randomized to SMAD3 knockdown or control lentivirus and were evaluated to assess longer-term effects on AVF diameter, patency and related measures at 30 days after AVF creation.In Phase 1, compared to controls, SMAD3 knockdown achieved a 75% reduction in the proportion of CD31+ endothelial cells co-expressing SMAD3 (p<0.001), and also a significant reduction in the extent of EndMT (p<0.05). In Phase 2, compared to controls, SMAD3 knockdown was associated with an increase in the minimum diameter of the venous limb of the AVF (1.56±1.66 versus 4.26±1.71mm, p<0.01) and a reduced degree of stenosis (p<0.01). Consistent with this, neointimal thickness was reduced in the SMAD3 knockdown group (0.88±0.51 versus 0.45±0.19mm, p<0.05). Furthermore, endothelial integrity (the proportion of luminal cells expressing endothelial markers) was improved in the SMAD3 knockdown group (p<0.05). CONCLUSIONS: EndMT inhibition in a preclinical AVF model by local SMAD3 knockdown using gene therapy led to reduced neointimal hyperplasia, increased endothelialization and a reduction in the degree of AVF stenosis. This provides important proof-of-concept to pursue this approach as a clinical strategy to improve the patency of AVFs and other vein grafts.

Sediment source and dose influence the larval performance of the threatened coral Orbicella faveolata.

The effects of turbidity and sedimentation stress on early life stages of corals are poorly understood, particularly in Atlantic species. Dredging operations, beach nourishment, and other coastal construction activities can increase sedimentation and turbidity in nearby coral reef habitats and have the potential to negatively affect coral larval development and metamorphosis, reducing sexual reproduction success. In this study, we investigated the performance of larvae of the threatened Caribbean coral species Orbicella faveolata exposed to suspended sediments collected from a reef site in southeast Florida recently impacted by dredging (Port of Miami), and compared it to the performance of larvae exposed to sediments collected from the offshore, natal reef of the parent colonies. In a laboratory experiment, we tested whether low and high doses of each of these sediment types affected the survival, settlement, and respiration of coral larvae compared to a no-sediment control treatment. In addition, we analyzed the sediments used in the experiments with 16S rRNA gene amplicon sequencing to assess differences in the microbial communities present in the Port versus Reef sediments, and their potential impact on coral performance. Overall, only O. faveolata larvae exposed to the high-dose Port sediment treatment had significantly lower survival rates compared to the control treatment, suggesting an initial tolerance to elevated suspended sediments. However, significantly lower settlement rates were observed in both Port treatments (low- and high-dose) compared to the control treatment one week after exposure, suggesting strong latent effects. Sediments collected near the Port also contained different microbial communities than Reef sediments, and higher relative abundances of the bacteria Desulfobacterales, which has been associated with coral disease. We hypothesize that differences in microbial communities between the two sediments may be a contributing factor in explaining the observed differences in larval performance. Together, these results suggest that the settlement success and survival of O. faveolata larvae are more readily compromised by encountering port inlet sediments compared to reef sediments, with potentially important consequences for the recruitment success of this species in affected areas.

Endothelial Heterogeneity in the Response to Autophagy Drives Small Vessel Muscularization in Pulmonary Hypertension.

BACKGROUND: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization. METHODS: EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy-related gene 7 (Atg7EN-KO). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers. RESULTS: In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic Atg7EN-KO mice or after ATG7 silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models. CONCLUSIONS: Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.

Collapse or distention of the perioptic space in children - What does it mean to pediatric radiologists? Comprehensive review of perioptic space evaluation.

The perioptic space comprises the subarachnoid space [SAS] of the optic nerve communicating with the SAS of the central nervous system. Pressure variations in the SAS of the central nervous system can be transmitted to the optic papilla through the perioptic space. Variations in the diameter of the perioptic space serve as an important indicator for select intracranial pathologies in the pediatric population. Though the perioptic space can be evaluated using various imaging modalities, MRI is considered highly effective due to its superior soft tissue resolution. With advancement in MR imaging techniques, high-resolution images of the orbits can provide improved visualization of the perioptic space. It is imperative for the pediatric radiologist to routinely assess the perioptic space on brain and orbit MR imaging, as it can prompt exploration for additional features associated with select intracranial pathologies, thus improving diagnostic accuracy. This article reviews basic anatomy of the perioptic space, current understanding of the CSF dynamics between the perioptic space and central nervous system SAS, various imaging modalities utilized in the assessment of the perioptic space, MRI sequences and the optimal parameters of specific sequences, normal appearance of the perioptic space on MR imaging, and various common pediatric pathologies which cause alteration in the perioptic space.

Non-coding RNAs to treat vascular smooth muscle cell dysfunction.

Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis and vein graft failure. Recent advances have unveiled a fascinating range of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. We also discuss the prospects and challenges associated with developing ncRNA-based therapies for this prevalent type of cardiovascular pathology.

An Indocyanine Green-Based Nanoprobe for In Vivo Detection of Cellular Senescence.

There is an urgent need to improve conventional cancer-treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo- or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self-assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy.

P2X7 receptor knockout does not alter renal function or prevent angiotensin II-induced kidney injury in F344 rats.

P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7, abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1ß release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.

Arachnoid cyst in the pediatric patient: What the radiologist needs to know.

Arachnoid cysts are the most common incidentally discovered intracranial lesions on imaging and the most common cystic intracranial lesions. They may be developmental or secondary. A relative lack of recent literature and any comprehensive radiological review on arachnoid cysts has led to a general lack of awareness among radiologists of symptomatic or complicated arachnoid cysts. This is particularly concerning in pediatric patients. While arachnoid cysts are asymptomatic in most cases, they can cause clinical symptoms in a minority of cases, especially when they occur in unusual sites. These include intraventricular locations where they may cause hydrocephalus, the basal cisterns where they may compress cranial nerves, the cerebellopontine angle where they have to be differentiated from a number of cystic lesions, the cavum septum pellucidum or cavum velum interpositum, the choroid fissure where they can entrap the temporal horn and compress the hippocampus, the posterior fossa where they need to be differentiated from other posterior fossa cystic lesions, and within the spinal canal where there is a concern for cord or nerve root compression. Larger cysts are more prone to complications such as mass effect, hemorrhage, and rupture. Hemorrhage and rupture often present with acute symptoms. Ruptured cysts lose their characteristic imaging appearance and can mimic several ominous pathologies. It therefore becomes vital to accurately diagnose these cases as complications of pre-existing arachnoid cysts for appropriate management. A detailed review of all diagnostic imaging aspects of arachnoid cysts will help fill in the existing information void on this important entity.

Control of endothelial cell function and arteriogenesis by MEG3:EZH2 epigenetic regulation of integrin expression.

Epigenetic processes involving long non-coding RNAs regulate endothelial gene expression. However, the underlying regulatory mechanisms causing endothelial dysfunction remain to be elucidated. Enhancer of zeste homolog 2 (EZH2) is an important rheostat of histone H3K27 trimethylation (H3K27me3) that represses endothelial targets, but EZH2 RNA binding capacity and EZH2:RNA functional interactions have not been explored in post-ischemic angiogenesis. We used formaldehyde/UV-assisted crosslinking ligation and sequencing of hybrids and identified a new role for maternally expressed gene 3 (MEG3). MEG3 formed the predominant RNA:RNA hybrid structures in endothelial cells. Moreover, MEG3:EZH2 assists recruitment onto chromatin. By EZH2-chromatin immunoprecipitation, following MEG3 depletion, we demonstrated that MEG3 controls recruitment of EZH2/H3K27me3 onto integrin subunit alpha4 (ITGA4) promoter. Both MEG3 knockdown or EZH2 inhibition (A-395) promoted ITGA4 expression and improved endothelial cell migration and adhesion to fibronectin in vitro. The A-395 inhibitor re-directed MEG3-assisted chromatin remodeling, offering a direct therapeutic benefit by increasing endothelial function and resilience. This approach subsequently increased the expression of ITGA4 in arterioles following ischemic injury in mice, thus promoting arteriogenesis. Our findings show a context-specific role for MEG3 in guiding EZH2 to repress ITGA4. Novel therapeutic strategies could antagonize MEG3:EZH2 interaction for pre-clinical studies.

Cardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes.

Despite tremendous progress in the development of mature heart-on-a-chip models, human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)-induced myocardial inflammation, as the presence of immune cells augmented the secretion of proinflammatory cytokines, triggered progressive impairment of contractile function, and altered intracellular calcium transients. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the heart-on-a-chip and then validated in COVID-19 patients with low left ventricular ejection fraction, demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation-induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2-induced myocardial inflammation, we established that administration of endothelial cell-derived exosomes effectively rescued the contractile deficit, normalized calcium handling, elevated the contraction force, and reduced the ccf-mtDNA and cytokine release via Toll-like receptor-nuclear factor κB signaling axis.

Bilateral nephrectomy impairs cardiovascular function and cerebral perfusion in a rat model of acute hemodilutional anemia.

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain Po2 (PBro2) in a rat model. Changes in PBro2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5-8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and PBro2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in PBro2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in PBro2. This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved PBro2. These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize PBro2 during acute anemia.NEW & NOTEWORTHY This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain Po2 (PBro2), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in PBro2, accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining PBro2 and initiating the increase in CO that optimized brain perfusion during acute anemia.

Endothelial to mesenchymal transition: at the axis of cardiovascular health and disease.

Endothelial cells (ECs) line the luminal surface of blood vessels and play a major role in vascular (patho)-physiology by acting as a barrier, sensing circulating factors and intrinsic/extrinsic signals. ECs have the capacity to undergo endothelial-to-mesenchymal transition (EndMT), a complex differentiation process with key roles both during embryonic development and in adulthood. EndMT can contribute to EC activation and dysfunctional alterations associated with maladaptive tissue responses in human disease. During EndMT, ECs progressively undergo changes leading to expression of mesenchymal markers while repressing EC lineage-specific traits. This phenotypic and functional switch is considered to largely exist in a continuum, being characterized by a gradation of transitioning stages. In this report, we discuss process plasticity and potential reversibility and the hypothesis that different EndMT-derived cell populations may play a different role in disease progression or resolution. In addition, we review advancements in the EndMT field, current technical challenges, as well as therapeutic options and opportunities in the context of cardiovascular biology.

Clonal Expansion in Cardiovascular Pathology.

Clonal expansion refers to the proliferation and selection of advantageous "clones" that are better suited for survival in a Darwinian manner. In recent years, we have greatly enhanced our understanding of cell clonality in the cardiovascular context. However, our knowledge of the underlying mechanisms behind this clonal selection is still severely limited. There is a transpiring pattern of clonal expansion of smooth muscle cells and endothelial cells-and, in some cases, macrophages-in numerous cardiovascular diseases irrespective of their differing microenvironments. These findings indirectly suggest the possible existence of stem-like vascular cells which are primed to respond during disease. Subsequent clones may undergo further phenotypic changes to adopt either protective or detrimental roles. By investigating these clone-forming vascular cells, we may be able to harness this inherent clonal nature for future therapeutic intervention. This review comprehensively discusses what is currently known about clonal expansion across the cardiovascular field. Comparisons of the clonal nature of vascular cells in atherosclerosis (including clonal hematopoiesis of indeterminate potential), pulmonary hypertension, aneurysm, blood vessel injury, ischemia- and tumor-induced angiogenesis, and cerebral cavernous malformations are evaluated. Finally, we discuss the potential clinical implications of these findings and propose that proper understanding and specific targeting of these clonal cells may provide unique therapeutic options for the treatment of these cardiovascular conditions.