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Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma ( CBL ) gene. She was treated with MEK inhibition with complete resolution of symptoms, near‐complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system. While patients with KLA have been reported to harbor mutations in NRAS , here we report for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition. Synopsis Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway. Identification of CBL mutation driving KLA. Patient successfully treated with MEK inhibition. Graphical Abstract Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway.

Anti‐angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor‐A (VEGF‐A) have revolutionized treatment of retinal vascular diseases including age‐related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti‐VEGF‐A monotherapy efficacy by targeting both VEGF‐A and angiopoietin‐2 (ANG‐2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF‐A. Simultaneous VEGF‐A and ANG‐2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain‐exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF‐A and ANG‐2. RG7716 showed greater efficacy than anti‐VEGF‐A alone in a non‐human primate laser‐induced CNV model after intravitreal delivery. Modification of RG7716's FcRn and FcγR binding sites disabled the antibodies' Fc‐mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential next‐generation therapy for neovascular indications of the eye. Synopsis The ratio of angiopoietins ANG‐1 and ANG‐2 regulates vessel quiescence and neoangiogenesis as well as barrier function. It also acts as a switch from health to neovascular eye diseases. ANG‐2, but not ANG‐1 levels are strongly upregulated in neovascular eye diseases. ANG‐2 works in concert with VEGF‐A to mediate pathological angiogenesis and endothelial dysfunction. Combined inhibition of ANG‐2 and VEGF‐A is more efficacious than anti‐VEGF‐A monotherapy in rodent models of choroidal neovascularization. The combination prevents vessel leakiness and neovascularization and its consequences such as increased retinal apoptosis or loss of retinal functionality. A bispecific antibody (CrossMAb RG7716) was generated with a modified Fc region optimized for use in ophthalmology. It reduced lesion severity better than anti‐VEGF‐A monotherapy in a laser‐induced model of CNV in non‐human primates. Graphical Abstract The ratio of angiopoietins ANG‐1 and ANG‐2 regulates vessel quiescence and neoangiogenesis as well as barrier function. It also acts as a switch from health to neovascular eye diseases.

Low‐flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3ca H1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K‐driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K‐driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low‐flow vascular malformations. SYNOPSIS This work describes a robust preclinical model of PI3K‐driven vascular malformations using the postnatal mouse retina. We show that AKT inhibition by miransertib is an effective therapeutic strategy for these diseases. Pik3ca H1047R mutation in endothelial cells leads to enhanced cell cycle progression. Active angiogenesis is required for the formation of PI3K‐driven vascular malformations. PI3K‐driven vascular malformations are prevented and regressed upon miransertib treatment. Graphical Abstract This work describes a robust preclinical model of PI3K‐driven vascular malformations using the postnatal mouse retina. We show that AKT inhibition by miransertib is an effective therapeutic strategy for these diseases.

Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels. These insulin‐secreting organoids exhibit a significantly higher angiogenic activity compared to freshly isolated islets, cultured islets, and non‐prevascularized islet organoids. This is caused by paracrine signaling between the β‐cells and the microvessels, mediated by insulin binding to its corresponding receptor on endothelial cells. In vivo , the prevascularized islet organoids are rapidly blood‐perfused after transplantation by the interconnection of their autochthonous microvasculature with surrounding blood vessels. As a consequence, a lower number of islet grafts are required to restore normoglycemia in diabetic mice. Thus, prevascularized islet organoids may be used to improve the success rates of clinical islet transplantation. Synopsis This study introduces a novel strategy to accelerate the revascularization of transplanted islets by the fusion of microvascular fragments (MVF) with pancreatic islet cells. These prevascularized islet organoids may be used to improve the success rate of clinical islet transplantation. The fusion of islet cells with MVF resulted in compact prevascularized islet organoids. Prevascularized islet organoids exhibited a highly angiogenic activity, mediated by a paracrine signaling between β‐cells and endothelial cells. The transplantation of prevascularized islet organoids restored normoglycemia in diabetic animals immediately after transplantation. Graphical Abstract This study introduces a novel strategy to accelerate the revascularization of transplanted islets by the fusion of microvascular fragments (MVF) with pancreatic islet cells. These prevascularized islet organoids may be used to improve the success rate of clinical islet transplantation.

Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR. Synopsis Retinal pericyte loss, vascular leakage and neovascularization are the main pathological changes during Diabetic Retinopathy (DR). Here we show that Sema4D/PlexinB1 signaling critically contributes to these processes, and is a therapeutic target in this context. Sema4D was increased in aqueous fluid of DR patients and in retinas of several mouse DR models. Sema4D/PlexinB1 signaling induced both endothelial cell and pericyte dysfunction. Inhibition of Sema4D/PlexinB1 alleviated vascular dysfunction in DR models. Anti‐Sema4D and anti‐VEGF exhibited a synergistic therapeutic effect. Graphical Abstract Retinal pericyte loss, vascular leakage and neovascularization are the main pathological changes during Diabetic Retinopathy (DR). Here we show that Sema4D/PlexinB1 signaling critically contributes to these processes, and is a therapeutic target in this context.

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR‐21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR‐21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR‐21 expression influences foam cell formation, sensitivity to ER‐stress‐induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR‐21 in macrophages increases the expression of the miR‐21 target gene, MKK3, promoting the induction of p38‐CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post‐translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR‐21 in atherogenesis. Synopsis The present work defines the major contribution of miR‐21 in regulating macrophage inflammation, apoptosis, efferocytosis and lipid metabolism during atherogenesis. miR‐21 is the most abundant miRNA in macrophages. Lack of miR‐21 in the hematopoietic system accelerates atherogenesis and promotes adverse plaque remodeling. In the absence of miR‐21, macrophages exhibit a pro‐inflammatory phenotype, and their phagocytic activity is reduced. Deficiency of miR‐21 in macrophages induces ER‐stress‐mediated apoptosis and promotes activation of MKK3/p38 and JNK signaling pathways. Lack of miR‐21 in macrophages promotes the degradation of ABCG1, impairing the efflux of cholesterol and increasing the foam cell formation. Graphical Abstract The present work defines the major contribution of miR‐21 in regulating macrophage inflammation, apoptosis, efferocytosis and lipid metabolism during atherogenesis.

The FZD4:LRP5:TSPAN12 receptor complex is activated by the secreted protein Norrin in retinal endothelial cells and leads to βcatenin‐dependent formation of the blood–retina–barrier during development and its homeostasis in adults. Mutations disrupting Norrin signaling have been identified in several congenital diseases leading to hypovascularization of the retina and blindness. Here, we developed F4L5.13, a tetravalent antibody designed to induce FZD4 and LRP5 proximity in such a way as to trigger βcatenin signaling. Treatment of cultured endothelial cells with F4L5.13 rescued permeability induced by VEGF in part by promoting surface expression of junction proteins. Treatment of Tspan12 −/− mice with F4L5.13 restored retinal angiogenesis and barrier function. F4L5.13 treatment also significantly normalized neovascularization in an oxygen‐induced retinopathy model revealing a novel therapeutic strategy for diseases characterized by abnormal angiogenesis and/or barrier dysfunction. SYNOPSIS This study reports a FZD4:LRP5 antibody agonist (F4L5.13) that activates βcatenin signaling in endothelial cells. F4L5.13 shows efficacy in animal models by normalizing defective retinal angiogenesis and barrier function, providing a novel therapeutic strategy for eye diseases. βcatenin signaling was activated by F4L5.13, which functions as a Norrin surrogate in endothelial cells. Endothelial barrier function was promoted, and VEGF‐induced endothelial permeability was blocked by F4L5.13. Retinal barrier function was restored by F4L5.13 in Tspan12 −/− mice. Pathological neovascularization was reduced by F4L5.13 in an OIR model. Graphical Abstract This study reports a FZD4:LRP5 antibody agonist (F4L5.13) that activates βcatenin signaling in endothelial cells. F4L5.13 shows efficacy in animal models by normalizing defective retinal angiogenesis and barrier function, providing a novel therapeutic strategy for eye diseases.

Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate‐restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl‐CoA:3‐oxoacid‐CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high‐fat, low‐carbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases. Synopsis Vascular endothelial cells are shown to be capable of taking up and oxidizing ketone bodies, which enhances cell proliferation, migration and vessel sprouting. Expression of SCOT, the key enzyme for ketone body oxidation, was detected in endothelial cells from different vascular beds. Endothelial cells can oxidize ketone bodies to generate acetyl‐CoA, biomass and ATP. Ketone bodies stimulate proliferation and tube formation of cultured endothelial cells. Ketogenic diet transiently increases endothelial cell proliferation in the heart and prevents capillary rarefication in a model of cardiac hypertrophy. Graphical Abstract Vascular endothelial cells are shown to be capable of taking up and oxidizing ketone bodies, which enhances cell proliferation, migration and vessel sprouting.

Metastasis is the main cause of deaths related to solid cancers. Active transcriptional programmes are known to regulate the metastatic cascade but the molecular determinants of metastatic colonization remain elusive. Using an inducible piggyBac (PB) transposon mutagenesis screen, we have shown that overexpression of the transcription factor nuclear factor IB (NFIB) alone is sufficient to enhance primary mammary tumour growth and lung metastatic colonization. Mechanistically and functionally, NFIB directly increases expression of the oxidoreductase ERO1A , which enhances HIF1α‐VEGFA‐mediated angiogenesis and colonization, the last and fatal step of the metastatic cascade. NFIB is thus clinically relevant: it is preferentially expressed in the poor‐prognostic group of basal‐like breast cancers, and high expression of the NFIB/ERO1A/VEGFA pathway correlates with reduced breast cancer patient survival. Synopsis Transcriptional factor nuclear factor IB (NFIB) is sufficient to enhance lung metastatic colonization via enhanced angiogenesis, thus revealing a targetable network that promotes breast cancer colonization. NFIB was identified via an unbiased ex vivo piggyBac (PB) transposon insertional mutagenesis screen, and validated as an inducer of metastatic colonization in breast cancer. NFIB directly enhances ERO1A oxidoreductase expression, which in turn increases intracellular ROS levels, stabilizes HIF1alpha protein in the nucleus and upregulates VEGFA expression. Functionally, the NFIB‐ERO1A‐VEGFA axis enhances angiogenesis, promotes metastatic colonization and shortens overall survival of the animals. A correlation was found between NFIB, ERO1A, and VEGFA co‐expression and the metastatic potential in PDX models. Graphical Abstract Transcriptional factor nuclear factor IB (NFIB) is sufficient to enhance lung metastatic colonization via enhanced angiogenesis, thus revealing a targetable network that promotes breast cancer colonization.

Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress‐mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM. A basal autophagy process has recently been described as playing an important role in normal platelet activation. We now report a substantial mitophagy induction (above basal autophagy levels) in diabetic platelets, suggesting alternative roles for autophagy in platelet pathology. Using a combination of molecular, biochemical, and imaging studies on human DM platelets, we report that platelet mitophagy induction serves as a platelet protective mechanism that responds to oxidative stress through JNK activation. By removing damaged mitochondria (mitophagy), phosphorylated p53 is reduced, preventing progression to apoptosis, and preserving platelet function. The absence of mitophagy in DM platelets results in failure to protect against oxidative stress, leading to increased thrombosis. Surprisingly, this removal of damaged mitochondria does not require contributions from transcription, as platelets lack a nucleus. The considerable energy and resources expended in “prepackaging” the complex mitophagy machinery in a short‐lived normal platelet support a critical role, in anticipation of exposure to oxidative stress. Synopsis Under conditions of the severe oxidative stress commonly associated with diabetes mellitus in patients, induction of platelet mitophagy protects the platelet from apoptosis by removing the damaged mitochondria and preserves platelets function. Autophagy and mitophagy are increased in diabetic platelets. Mitophagy is induced in platelets through an ROS/JNK‐mediated pathway. Mitophagy induction serves to protect diabetic platelets from oxidative stress‐induced apoptosis. Mitophagy induction protects against increased thrombosis associated with diabetes mellitus. Graphical Abstract Under conditions of the severe oxidative stress commonly associated with diabetes mellitus in patients, induction of platelet mitophagy protects the platelet from apoptosis by removing the damaged mitochondria and preserves platelets function.