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Brain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in the RAS-MAPK signaling pathway. Leveraging these genetic discoveries, preclinical mouse models have been developed to uncover the mechanisms underlying abnormal vessel formation, and thus revealing potential therapeutic targets. Impressively, initial preclinical studies suggest that pharmacological treatments disrupting these aberrant pathways may ameliorate the abnormal pathologic vessel remodeling and inflammatory and hemorrhagic nature of these high-flow vascular anomalies. Intriguingly, these studies also suggest uncontrolled angiogenic signaling may be a major driver in bAVM pathogenesis. This comprehensive review describes the genetics underlying both inherited and sporadic bAVM and details the state of the field regarding murine models of bAVM, highlighting emerging therapeutic targets that may transform our approach to treating these devastating lesions., Competing Interests: Declarations. Competing interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known., Methods: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 ( Alk1 ) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib., Results: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations., Conclusions: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT., Competing Interests: None.

Now a day's liquid biodiesel fuels utilization that are produced from renewable natural resources such as moringa oleifera seeds using transesterification method accounts among the best alternative option for substituting conventional fossil fuels. This investigation shows production of biodiesel from moringa oleifera seeds by transesterification process with an additive of diethyl ether (DEE2%). It also finds out the efficiency and emission analysis of three fuels namely pure diesel, B20 (20% moringa blended with 80% diesel), and B20DEE2% (20% Moringa &2%DEE additive blended with 78% diesel) compression ignition engine using single cylinder, 4-stroke direct injection method. The observations of the fuel characterization show that B20 and B20DEE2% biodiesel blended fuels have nearly equal characteristics such as viscosity, density, and calorific values that compared to diesel fuel. Moreover, these fuels have comparable performance such as brake thermal efficiency, brake power, brake torque, and specific fuel consumption compared to clear diesel fuel, and especially B20DEE2% have better emission condition than B20 biodiesel blend fuel., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the adult SVZ control NSC behavior are unclear. We found that Cx43 is highly expressed by SVZ NSCs and ECs, and its deletion in either leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by single-cell RNA sequencing and in vitro studies showing that ECs control NSC proliferation by regulating expression of genes associated with NSC quiescence and/or activation in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights inform adult NSC regulation and maintenance aimed at stem cell therapies for neurodegenerative disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

During blood vessel development, endothelial cells become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Arterial-venous specification occurs in conjunction with suppression of endothelial cell cycle progression; however, the mechanistic role of cell cycle state is unknown. Herein, using Cdh5-CreER T2 ;R26FUCCI2aR reporter mice, we find that venous endothelial cells are enriched for the FUCCI-Negative state (early G1) and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state (late G1) and TGF-β signaling. Furthermore, early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-β1-induced arterial gene expression. Pharmacologically induced cell cycle arrest prevents arterial-venous specification defects in mice with endothelial hyperproliferation. Collectively, our results show that distinct endothelial cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous fate., (© 2022. The Author(s).)

The use of neural stem cell (NSC) therapy for the treatment of stroke patients is successfully paving its way into advanced phases of large-scale clinical trials. To understand how to optimize NSC therapeutic approaches, it is fundamental to decipher the crosstalk between NSC and other cells that comprise the NSC microenvironment (niche) and regulate their function, in vivo ; namely, the endothelial cells of the microvasculature. In this mini review, we first provide a concise summary of preclinical findings describing the signaling mechanisms between NSC and vascular endothelial cells and vice versa . Second, we describe the progress made in the development of NSC therapy for the treatment of strokes.

The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial, and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in the heart and lungs, and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH.Expressions of Cx37, Cx40 and Cx43 were studied in lung specimens from patients with idiopathic pulmonary arterial hypertension (IPAH) or PH associated with chronic hypoxaemic lung diseases (chronic hypoxia-induced pulmonary hypertension (CH-PH)). Heterozygous Cx43 knockdown CD1 (Cx43 +/- ) and wild-type littermate (Cx43 +/+ ) mice at 12 weeks of age were randomly divided into two groups, one of which was maintained in room air and the other exposed to hypoxia (10% oxygen) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PAs), lung inflammation and PA vasoreactivity.Cx43 levels were increased in PAs from CH-PH patients and decreased in PAs from IPAH patients; however, no difference in Cx37 or Cx40 levels was noted. Upon hypoxia treatment, the Cx43 +/- mice were partially protected against CH-PH when compared to Cx43 +/+ mice, with reduced pulmonary arterial muscularisation and inflammatory infiltration. Interestingly, the adaptive changes in cardiac remodelling in Cx43 +/- mice were not affected. PA contraction due to endothelin-1 (ET-1) was increased in Cx43 +/- mice under normoxic and hypoxic conditions.Taken together, these results indicate that targeting Cx43 may have beneficial therapeutic effects in PH without affecting compensatory cardiac hypertrophy., Competing Interests: Conflict of interest: C. Bouvard has nothing to disclose. Conflict of interest: N. Genet has nothing to disclose. Conflict of interest: C. Phan has nothing to disclose. Conflict of interest: B. Rode has nothing to disclose. Conflict of interest: R. Thuillet has nothing to disclose. Conflict of interest: L. Tu has nothing to disclose. Conflict of interest: P. Robillard has nothing to disclose. Conflict of interest: M. Campagnac has nothing to disclose. Conflict of interest: R. Soleti has nothing to disclose. Conflict of interest: E. Dumas De La Roque has nothing to disclose. Conflict of interest: F. Delcambre has nothing to disclose. Conflict of interest: L. Cronier has nothing to disclose. Conflict of interest: T. Parpaite has nothing to disclose. Conflict of interest: E. Maurat has nothing to disclose. Conflict of interest: P. Berger reports grants from Nycomed, Takeda, Fondation du Souffle and Fonds de Dotation Recherche en Santé Respiratoire, during the conduct of the study; grants and personal fees for lectures, advisory board work and travel to meetings from Novartis, personal fees for lectures and non-financial (travel) support from Chiesi, grants and personal fees for advisory board work and lectures, as well as non-financial (travel) support from Boehringer Ingelheim, personal fees for advisory board work and lectures, as well as non-financial (travel) support from AstraZeneca and Sanofi, personal fees for advisory board work and lectures from Menarini, and personal fees for lectures from TEVA, outside the submitted work. Conflict of interest: J-P. Savineau has nothing to disclose. Conflict of interest: R. Marthan has nothing to disclose. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: V. Freund-Michel has nothing to disclose. Conflict of interest: C. Guibert has nothing to disclose., (Copyright ©ERS 2020.)

Stem cell therapies demonstrate promising results as treatment for neurological disease and injury, owing to their innate ability to enhance endogenous neural tissue repair and promote functional recovery. However, delivery of undifferentiated and viable neuronal stem cells requires an engineered delivery system that promotes integration of transplanted cells into the inflamed and cytotoxic region of damaged tissue. Within the brain, endothelial cells (EC) of the subventricular zone play a critical role in neural stem cell (NSC) maintenance, quiescence and survival. Therefore, here, we describe the use of polyethylene glycol microbeads for the coincident delivery of EC and NSC as a means of enhancing appropriate NSC quiescence and survival during transplantation into the mouse brain. We demonstrate that EC and NSC co-encapsulation maintained NSC quiescence, enhanced NSC viability, and facilitated NSC extravasation in vitro, as compared to NSC encapsulated alone. In addition, co-encapsulated cells delivered to an in vivo non-injury model reduced inflammatory response compared to freely injected NSC. These results suggest the strong potential of a biomimetic engineered niche for NSC delivery into the brain following neurological injury.

Endothelial cell migration, proliferation and survival are triggered by VEGF-A activation of VEGFR2. However, how these cell behaviors are regulated individually is still unknown. Here we identify Endophilin-A2 (ENDOA2), a BAR-domain protein that orchestrates CLATHRIN-independent internalization, as a critical mediator of endothelial cell migration and sprouting angiogenesis. We show that EndoA2 knockout mice exhibit postnatal angiogenesis defects and impaired front-rear polarization of sprouting tip cells. ENDOA2 deficiency reduces VEGFR2 internalization and inhibits downstream activation of the signaling effector PAK but not ERK, thereby affecting front-rear polarity and migration but not proliferation or survival. Mechanistically, VEGFR2 is directed towards ENDOA2-mediated endocytosis by the SLIT2-ROBO pathway via SLIT-ROBO-GAP1 bridging of ENDOA2 and ROBO1. Blocking ENDOA2-mediated endothelial cell migration attenuates pathological angiogenesis in oxygen-induced retinopathy models. This work identifies a specific endocytic pathway controlling a subset of VEGFR2 mediated responses that could be targeted to prevent excessive sprouting angiogenesis in pathological conditions.

Purpose of Review: Considerable progress has been made in the field of stem cell research; nonetheless, the use of stem cells for regenerative medicine therapies, for either endogenous tissue repair or cellular grafts post injury, remains a challenge. To better understand how to maintain stem cell potential in vivo and promote differentiation ex vivo, it is fundamentally important to elucidate the interactions between stem cells and their surrounding partners within their distinct niches., Recent Findings: Among the vast array of proteins depicted as mediators for cell-to-cell interactions, connexin-comprised gap junctions play pivotal roles in the regulation of stem cell fate both in vivo and in vitro., Summary: This review summarizes and illustrates the current knowledge regarding the multifaceted roles of Cx43, specifically, in various stem cell niches., Competing Interests: Compliance with Ethical StandardsNafiisha Genet, Neha Bhatt, Antonin Bourdieu, and Karen K. Hirschi declare that they have no conflict of interest.This article does not contain any studies with human or animal subjects performed by any of the authors.

Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion ([Formula: see text]) is commonly associated to cellular damages due to [Formula: see text] overproduction, we previously demonstrated that, in physiological conditions, [Formula: see text] also participates to the 5-HT contraction in intrapulmonary arteries (IPA). Here, we focused on the signaling pathways leading to [Formula: see text] production in response to 5-HT in rat IPA. Using electron paramagnetic resonance on rat IPA, we showed that 5-HT (100 μM)-induced [Formula: see text] production was inhibited by ketanserin (1 μM-an inhibitor of the 5-HT 2 receptor), absence of extracellular calcium, two blockers of voltage-independent calcium permeable channels (RHC80267 50 μM and LOE-908 10 μM) and a blocker of the mitochondrial complex I (rotenone-100 nM). Depletion of calcium from the sarcoplasmic reticulum or nicardipine (1 μM-an inhibitor of the L-type voltage-dependent calcium channel) had no effect on the 5-HT-induced [Formula: see text] production. [Formula: see text] levels were also increased by α-methyl-5-HT (10 μM-a 5-HT 2 receptors agonist) whereas GR127935 (1 μM-an antagonist of the 5-HT 1B/D receptor) and citalopram (1 μM-a 5-HT transporter inhibitor) had no effect on the 5-HT-induced [Formula: see text] production. Peroxynitrites were increased in response to 5-HT (100 μM). In isolated pulmonary arterial smooth muscle cells loaded with rhod-2 or mitosox probes, we respectively showed that 5-HT increased both mitochondrial calcium and [Formula: see text] levels, which were both abrogated in absence of extracellular calcium. Mitochondrial [Formula: see text] levels were also abolished in the presence of rotenone (100 nM). In pulmonary arterial smooth muscle cells loaded with TMRM, we showed that 5-HT transiently depolarized the mitochondrial membrane whereas in the absence of extracellular calcium the mitochondrial membrane depolarisation was delayed and sustained in response to 5-HT. 5-HT decreased the mitochondrial respiratory rate measured with a Clark oxygen electrode. Altogether, in physiological conditions, 5-HT acts on 5-HT 2 receptors and induces an [Formula: see text] production dependent on extracellular calcium and mitochondria.

The involvement of governments in the home care sector strongly varies across Europe. This study aims to explain the differences through the conditions for the involvement of informal care and governments in society; wealth and the demographic structure. As this study could combine qualitative data and quantitative data analyses, it could consider larger patterns than previous studies which were often based on ideographic historical accounts. Extensive data were gathered in 30 European countries, between 2008 and 2010. In each country, policy documents were analysed and experts were interviewed. International variation in regulation and governmental funding of personal care and domestic aid are associated with differences in prevailing values on family care, tax burden and wealth in a country. Hence, this study provides evidence for the obstacles - i.e. country differences - for transferring home care policies between countries. However, longitudinal research is needed to establish whether this is indeed the causal relationship we expect., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Health and social services provided at home are becoming increasingly important. Hence, there is a need for information on home care in Europe. The objective of this literature review was to respond to this need by systematically describing what has been reported on home care in Europe in the scientific literature over the past decade., Methods: A systematic literature search was performed for papers on home care published in English, using the following data bases: Cinahl, the Cochrane Library, Embase, Medline, PsycINFO, Sociological Abstracts, Social Services Abstracts, and Social Care Online. Studies were only included if they complied with the definition of home care, were published between January 1998 and October 2009, and dealt with at least one of the 31 specified countries. Clinical interventions, instrument developments, local projects and reviews were excluded. The data extracted included: the characteristics of the study and aspects of home care 'policy & regulation', 'financing', 'organisation & service delivery', and 'clients & informal carers'., Results: Seventy-four out of 5,133 potentially relevant studies met the inclusion criteria, providing information on 18 countries. Many focused on the characteristics of home care recipients and on the organisation of home care. Geographical inequalities, market forces, quality and integration of services were also among the issues frequently discussed., Conclusions: Home care systems appeared to differ both between and within countries. The papers included, however, provided only a limited picture of home care. Many studies only focused on one aspect of the home care system and international comparative studies were rare. Furthermore, little information emerged on home care financing and on home care in general in Eastern Europe. This review clearly shows the need for more scientific publications on home care, especially studies comparing countries. A comprehensive and more complete insight into the state of home care in Europe requires the gathering of information using a uniform framework and methodology.