Specific Requirement of the p84/p110γ Complex of PI3Kγ for Antibody-Activated, Inducible Cross-Presentation in Murine Type 2 DCs.

Cross-presentation by MHCI is optimally efficient in type 1 dendritic cells (DC) due to their high capacity for antigen processing. However, through specific pathways, other DCs, such as type 2 DCs and inflammatory DCs (iDCs) can also cross-present antigens. FcγR-mediated uptake by type 2 DC and iDC subsets mediates antibody-dependent cross-presentation and activation of CD8 T cell responses.

A minor tweak in transplant surgery protocols alters the cellular landscape of the arterial wall during transplant vasculopathy.

Introduction: Transplant vasculopathy (TV) is a major complication after solid organ transplantation, distinguished by an arterial intimal thickening that obstructs the vascular lumen and leads to organ rejection. To date, TV remains largely untreatable, mainly because the processes involved in its development remain unclear. Aortic transplantation in mice, used to mimic TV, relies on highly variable experimental protocols, particularly regarding the type of anastomosis used to connect the donor aorta to the recipient.

PI3KCIIα-Dependent Autophagy Program Protects From Endothelial Dysfunction and Atherosclerosis in Response to Low Shear Stress in Mice.

Background: The ability to respond to mechanical forces is a basic requirement for maintaining endothelial cell (ECs) homeostasis, which is continuously subjected to low shear stress (LSS) and high shear stress (HSS). In arteries, LSS and HSS have a differential impact on EC autophagy processes. However, it is still unclear whether LSS and HSS differently tune unique autophagic machinery or trigger specific autophagic responses in ECs.

Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification.

Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood.

The different natural estrogens promote endothelial healing through distinct cell targets.

The main estrogen, 17β-estradiol (E2), exerts several beneficial vascular actions through estrogen receptor α (ERα) in endothelial cells. However, the impact of other natural estrogens such as estriol (E3) and estetrol (E4) on arteries remains poorly described. In the present study, we report the effects of E3 and E4 on endothelial healing after carotid artery injuries in vivo.

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.

Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as β-adrenergic receptor (β-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β-ARs in airway structural and inflammatory cells.

A historical view of estrogen effect on arterial endothelial healing: From animal models to medical implication.

Endothelial barrier integrity is required for maintaining vascular homeostasis and fluid balance between the circulation and surrounding tissues. In contrast, abnormalities of endothelial cell function and loss of the integrity of the endothelial monolayer constitute a key step in the onset of atherosclerosis. Endothelial erosion is directly responsible for thrombus formation and cardiovascular events in about one-third of the cases of acute coronary syndromes.

Neuraminidases 1 and 3 Trigger Atherosclerosis by Desialylating Low-Density Lipoproteins and Increasing Their Uptake by Macrophages.

Background Chronic vascular disease atherosclerosis starts with an uptake of atherogenic modified low-density lipoproteins (LDLs) by resident macrophages, resulting in formation of arterial fatty streaks and eventually atheromatous plaques. Increased plasma sialic acid levels, increased neuraminidase activity, and reduced sialic acid LDL content have been previously associated with atherosclerosis and coronary artery disease in human patients, but the mechanism underlying this association has not been explored. Methods and Results We tested the hypothesis that neuraminidases contribute to development of atherosclerosis by removing sialic acid residues from glycan chains of the LDL glycoprotein and glycolipids.

Tamoxifen Accelerates Endothelial Healing by Targeting ERα in Smooth Muscle Cells.

Rationale: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. It acts as an ER (estrogen receptor) α antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17β-estradiol in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear.

A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage.

Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme.

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress.

Cells subjected to stress situations mobilize specific membranes and proteins to initiate autophagy. Phosphatidylinositol-3-phosphate (PI3P), a crucial lipid in membrane dynamics, is known to be essential in this context. In addition to nutriments deprivation, autophagy is also triggered by fluid-flow induced shear stress in epithelial cells, and this specific autophagic response depends on primary cilium (PC) signaling and leads to cell size regulation.

Immune and Smooth Muscle Cells Interactions in Atherosclerosis: How to Target a Breaking Bad Dialogue?

Inflammation is a well-known pathophysiological factor of atherosclerosis but its therapeutic targeting has long been ignored. However, recent advances in the understanding of the immune mechanisms implicated in atherosclerosis have unveiled several therapeutic targets currently undergoing clinical trials. These studies have also shed light on a dialogue between the immune compartment and vascular smooth muscle cells (VSMCs) that plays a critical role in atherosclerotic disease initiation, progression, and stabilization.

Role of reactive oxygen species in atherosclerosis: Lessons from murine genetic models.

Atherosclerosis is a multifactorial chronic and inflammatory disease of medium and large arteries, and the major cause of cardiovascular morbidity and mortality worldwide. The pathogenesis of atherosclerosis involves a number of risk factors and complex events including hypercholesterolemia, endothelial dysfunction, increased permeability to low density lipoproteins (LDL) and their sequestration on extracellular matrix in the intima of lesion-prone areas. These events promote LDL modifications, particularly by oxidation, which generates acute and chronic inflammatory responses implicated in atherogenesis and lesion progression.

Elastic fibers and elastin receptor complex: Neuraminidase-1 takes the center stage.

Extracellular matrix (ECM) has for a long time being considered as a simple architectural support for cells. It is now clear that ECM presents a fundamental influence on cells driving their phenotype and fate. This complex network is highly specialized and the different classes of macromolecules that comprise the ECM determine its biological functions.

Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response.

Aims: Defects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization.

Small GTPases orchestrate cell-cell communication during collective cell movement.

Collective cell migration is a critical mechanism involved in cell movement during various physiological and pathological processes such as angiogenesis and metastasis formation. During collective movement, cells remain functionally connected and can coordinate individual cell behaviors to ensure efficient migration. A cell-cell communication process ensures this complex coordination.

PI3K and Calcium Signaling in Cardiovascular Disease.

Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca) fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear.

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors.

Background/aims: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F1-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival.

Matrix ageing and vascular impacts: focus on elastin fragmentation.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing.

The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells.

Rationale: 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor α (ERα) via 2 activation functions, AF1 and AF2, and can also activate membrane ERα. The role of E2 on the endothelium relies on membrane ERα activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMCs) are not fully understood.

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms.

Cardiovascular diseases are the most common cause of death around the world. This includes atherosclerosis and the adverse effects of its treatment, such as restenosis and thrombotic complications. The development of these arterial pathologies requires a series of highly-intertwined interactions between immune and arterial cells, leading to specific inflammatory and fibroproliferative cellular responses.

PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling.

In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes and whether isoform-selective interplays exist is currently unclear. Here we report that insulin signalling triggers the association of the liver-specific class II PI3K isoform γ (PI3K-C2γ) with Rab5-GTP, and its recruitment to Rab5-positive early endosomes.

Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport.

Aims: High-density lipoproteins (HDLs) protect against atherosclerosis mainly due to their function in hepatobiliary reverse cholesterol transport (RCT). This is a process whereby excess cholesterol from peripheral tissues is transported by HDL particles to the liver for further metabolism and biliary excretion. Hepatic uptake of HDL holoparticles involves the P2Y13 receptor, independently of the selective cholesteryl ester uptake mediated by scavenger receptor class B, type I (SR-BI).