Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in approximately half of sporadic (non-familial) VMs, with the cause of the remaining cases unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully

Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch–PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis.

Highlights d OPA1 is upregulated in response to angiogenic stimuli to limit NFkB signaling d OPA1 controls cytosolic Ca 2+ levels, NFkB signaling, and angiogenic gene expression d Deletion of endothelial Opa1 curtails tumor angiogenesis, growth, and metastatization d MYLS22, first-in-class small molecule, inhibits OPA1 and limits tumor growth

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release.

Summary Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca 2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca 2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca 2+ homeostasis, and WAT lipolysis in the regulation of energy balance.

Cs line the lumen of the entire vascular system and regulate the dynamic passage of materials and cells. They are located ubiquitously over a uniquely large surface of 4,000-7,000 m 2 covering the interface between the blood and tissues 1 . This vast contact area permits precise environmental sensing, nutrient transport and signaling integration from surrounding tissues. Therefore, ECs are regarded as the nutrient gatekeepers of the organism. Despite of this, the role of ECs in the regulation of systemic metabolism and as potential mediators of metabolic disorders remains enigmatic 2,3 .Adult ECs are largely quiescent except in some metabolic tissues where vascular expansion is considered the direct response to tissue requirements. This is the case for WAT during lipid accumulation 2 or muscle during exercise 4,5 in which adaptations to tissue function are accompanied by vascular growth. ECs mainly expand by angiogenesis, a process in which ECs sprout, branch, connect and remodel into functional vessel circuits 6,7 . Angiogenesis is guided by several extracellular cues, including growth factors, mechanical forces, flow and extracellular matrix proteins that collectively converge on intracellular growth pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR and RAS/MAPK/ERK 7,8 . Despite ECs being the first line of nutrient sensing and distribution, the role of nutrients in relation to angiogenesis and their potential impact in pathophysiology is unclear.PTEN (phosphatase and tensin homolog) is a lipid phosphatase that dephosphorylates membrane phospholipids generated by the class I PI3Ks 9,10 , the so-called phosphatidylinositol

Highlights d Acute western diet impairs memory performance, which is reversed by pregnenolone d Pregnenolone synthesis interference in POMC neurons causes cognitive dysfunction d POMC pregnenolone mediates memory function via hippocampal mechanisms d Pregnenolone in the CSF of individuals with unhealthy obesity correlates with cognitive score

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