Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood-retina barrier integrity.

The integrity of the blood-retina barrier (BRB) is crucial for phototransduction and vision, by tightly restricting transport of molecules between the blood and surrounding neuronal cells. Breakdown of the BRB leads to the development of retinal diseases. Here, we show that Netrin-1/Unc5b and Norrin/Lrp5 signaling establish a zonated endothelial cell gene expression program that controls BRB integrity.

Early exposure to Western Diet exacerbates visual outcomes in female mice.

Obesity, a growing pandemic in Western societies, significantly impacts metabolic health and contributes to visual disorders. While the systemic consequences of obesity, such as chronic inflammation and insulin resistance, are well-studied in adults, its early-life effects on retinal health remain underexplored. Using a maternal Western Diet (WD) exposure model, we investigated the developmental impact of early-life metabolic disturbances on retinal and cognitive function.

PIEZO1 overexpression in hereditary hemorrhagic telangiectasia arteriovenous malformations.

Background: Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function mutations in Activin receptor-like kinase 1 (ALK1) cause type 2 HHT and knockout (KO) mice develop AVMs due to overactivation of VEGFR2/PI3K/AKT signaling pathways. However, the full spectrum of signaling alterations in mutants remains unknown and means to combat AVM formation in patients are yet to be developed.

Shroom3-Rock interaction and profibrotic function: Resolving mechanism of an intronic CKD risk allele.

Common intronic enhancer SNPs in Shroom3 associate with CKD in GWAS, although there is paucity of detailed mechanism. Previously, we reported a role for Shroom3 in mediating crosstalk between TGFβ1- & Wnt/Ctnnb1 pathways promoting renal fibrosis (TIF). However, beneficial roles for Shroom3 in proteinuria have also been reported suggesting pleiotropic effects.

Endothelial Rho kinase controls blood vessel integrity and angiogenesis.

Background: The Rho kinases 1 and 2 (ROCK1/2) are serine-threonine specific protein kinases that control actin cytoskeleton dynamics. They are expressed in all cells throughout the body, including cardiomyocytes, smooth muscle cells and endothelial cells, and intimately involved in cardiovascular health and disease. Pharmacological ROCK inhibition is beneficial in mouse models of hypertension, atherosclerosis, and neointimal thickening that display overactivated ROCK.

Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells.

Roundabout (ROBO) 1 and 2 are transmembrane receptors that bind secreted SLIT ligands through their extracellular domains (ECDs) and signal through their cytoplasmic domains to modulate the cytoskeleton and regulate cell migration, adhesion, and proliferation. SLIT-ROBO signaling regulates pathological ocular neovascularization, which is a major cause of vision loss worldwide, but pharmacological tools to prevent SLIT-ROBO signaling are lacking. Here, we developed human monoclonal antibodies (mAbs) against the ROBO1 and ROBO2 ECDs.

Zonation and ligand and dose dependence of sphingosine 1-phosphate receptor-1 signalling in blood and lymphatic vasculature.

Aims: Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for the endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet, as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC autonomous S1P production, it is unclear if relative reductions in circulating S1P can cause endothelial dysfunction. It is also unclear how EC S1PR1 insufficiency, whether induced by deficiency in circulating ligand or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets.

The interactions between energy homeostasis and neurovascular plasticity.

Food intake and energy expenditure are sensed and processed by multiple brain centres to uphold energy homeostasis. Evidence from the past decade points to the brain vasculature as a new critical player in regulating energy balance that functions in close association with the local neuronal networks. Nutritional imbalances alter many properties of the neurovascular system (such as neurovascular coupling and blood-brain barrier permeability), thus suggesting a bidirectional link between the nutritional milieu and neurovascular health.

ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature.

The proliferation of the endothelium is a highly coordinated process to ensure the emergence, expansion, and homeostasis of the vasculature. While Bone Morphogenetic Protein (BMP) signaling fine-tunes the behaviors of endothelium in health and disease, how BMP signaling influences the proliferation of endothelium and therefore, modulates angiogenesis remains largely unknown. Here, we evaluated the role of Activin A Type I Receptor (ACVR1/ALK2), a key BMP receptor in the endothelium, in modulating the proliferation of endothelial cells.

Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching.

Notch signaling guides vascular development and function by regulating diverse endothelial cell behaviors, including migration, proliferation, vascular density, endothelial junctions, and polarization in response to flow. Notch proteins form transcriptional activation complexes that regulate endothelial gene expression, but few of the downstream effectors that enable these phenotypic changes have been characterized in endothelial cells, limiting our understanding of vascular Notch activities. Using an unbiased screen of translated mRNA rapidly regulated by Notch signaling, we identified novel in vivo targets of Notch signaling in neonatal mouse brain endothelium, including UNC5B, a member of the netrin family of angiogenic-regulatory receptors.

Vascular development, remodeling and maturation.

The development of the vascular system is crucial in supporting the growth and health of all other organs in the body, and vascular system dysfunction is the major cause of human morbidity and mortality. This chapter discusses three successive processes that govern vascular system development, starting with the differentiation of the primitive vascular system in early embryonic development, followed by its remodeling into a functional circulatory system composed of arteries and veins, and its final maturation and acquisition of an organ specific semi-permeable barrier that controls nutrient uptake into tissues and hence controls organ physiology. Along these steps, endothelial cells forming the inner lining of all blood vessels acquire extensive heterogeneity in terms of gene expression patterns and function, that we are only beginning to understand.

VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model.

Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice.

Complementary and Inducible creER Mouse Models for Functional Evaluation of Endothelial Cell Subtypes in the Bone Marrow.

In the adult bone marrow (BM), endothelial cells (ECs) are an integral component of the hematopoietic stem cell (HSC)-supportive niche, which modulates HSC activity by producing secreted and membrane-bound paracrine signals. Within the BM, distinct vascular arteriole, transitional, and sinusoidal EC subtypes display unique paracrine expression profiles and create anatomically-discrete microenvironments. However, the relative contributions of vascular endothelial subtypes in supporting hematopoiesis is unclear.

Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored.

Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy.

Background: Recently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress.

Effectiveness of Virtual Reality for Upper Extremity Function and Motor Performance of Children With Cerebral Palsy: A Systematic Review.

Importance: Research on the functional and motor performance impact of virtual reality (VR) as an intervention tool for children with cerebral palsy (CP) is limited.

Objective: To understand whether VR is an effective intervention to improve upper extremity (UE) function and motor performance of children diagnosed with CP.

Data Sources: Databases used in the search were EBSCOhost, One Search, PubMed, Cloud Source, CINAHL, SPORTDiscus, and Google Scholar.

Concurrent validity of smartphone-based markerless motion capturing to quantify lower-limb joint kinematics in healthy and pathological gait.

Markerless motion capturing has the potential to provide a low-cost and accessible alternative to traditional marker-based systems for real-world biomechanical assessment. However, before these systems can be put into practice, we need to rigorously evaluate their accuracy in estimating joint kinematics for various gait patterns. This study evaluated the accuracy of a low-cost, open-source, and smartphone-based markerless motion capture system, namely OpenCap, for measuring 3D joint kinematics in healthy and pathological gait compared to a marker-based system.

Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption.

Background: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood.

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes.

Unlabelled: Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice.

CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma.

Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C-C chemokine receptor type 7 (CCR7) and the chemokine (C-C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models.

Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice.

Low-density lipoprotein (LDL) accumulation in the arterial wall contributes to atherosclerosis initiation and progression. Activin A receptor-like type 1 (ACVRL1, called activin-like kinase receptor (ALK1)) is a recently identified receptor that mediates LDL entry and transcytosis in endothelial cells (ECs). However, the role of this pathway in vivo is not yet known.

Connexin 43-mediated neurovascular interactions regulate neurogenesis in the adult brain subventricular zone.

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.

Netrin-1 binding to Unc5B regulates Blood-Retina Barrier integrity.

Background: The blood brain barrier (BBB) preserves neuronal function in the central nervous system (CNS) by tightly controlling metabolite exchanges with the blood. In the eye, the retina is likewise protected by the blood-retina barrier (BRB) to maintain phototransduction. We showed that the secreted guidance cue Netrin-1 regulated BBB integrity, by binding to endothelial Unc5B and regulating canonical β-catenin dependent expression of BBB gene expression.