SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.

Purpose: Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm's canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity.

PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism.

PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT) in adult mice.

Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility.

Aldosterone blockade confers substantial cardiovascular and renal protection. The effects of aldosterone on mineralocorticoid receptors (MR) expressed in endothelial cells (EC) within the renal vasculature have not been delineated. We hypothesized that lack of MR in EC may be protective in renal vasculature and examined this by ablating the Nr3c2 gene in endothelial cells (EC-MR) in mice.

Glomerular endothelial cell maturation depends on ADAM10, a key regulator of Notch signaling.

The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10ΔEC mice).

Angiopoietin-1 is required for Schlemm's canal development in mice and humans.

Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway.

ShcA Adaptor Protein Promotes Nephrin Endocytosis and Is Upregulated in Proteinuric Nephropathies.

Nephrin is a key structural component of the podocyte slit diaphragm, and proper expression of nephrin on the cell surface is critical to ensure integrity of the blood filtration barrier. Maintenance of nephrin within this unique cell junction has been proposed to require dynamic phosphorylation events and endocytic recycling, although the molecular mechanisms that control this interplay are poorly understood. Here, we investigated the possibility that the phosphotyrosine adaptor protein ShcA regulates nephrin turnover.

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis.

Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD.

Angiopoietin-1 deficiency increases tumor metastasis in mice.

Background: Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Studies have shown that Angiopoietin-1 counteracts permeability induced by a number of stimuli. Here, we test the hypothesis that loss of Angiopoietin-1/Tek signaling in the vasculature would increase metastasis.

A novel assay to assess the effect of pharmaceutical compounds on the differentiation of podocytes.

Background And Purpose: Therapeutic options for treating glomerulopathies, the main cause of chronic kidney disease, are limited. Podocyte dedifferentiation is a major event in the pathogenesis of glomerulopathies. The goal of the present study was, therefore, to develop an assay to monitor podocyte differentiation suitable for compound screening.

Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.

Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria.

Vascular Growth Factors and Glomerular Disease.

The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier.

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture.

Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics.

Tubulovascular cross-talk by vascular endothelial growth factor a maintains peritubular microvasculature in kidney.

Vascular endothelial growth factor A (VEGFA) production by podocytes is critical for glomerular endothelial health. VEGFA is also expressed in tubular epithelial cells in kidney; however, its physiologic role in the tubule has not been established. Using targeted transgenic mouse models, we found that Vegfa is expressed by specific epithelial cells along the nephron, whereas expression of its receptor (Kdr/Vegfr2) is largely restricted to adjacent peritubular capillaries.

Loss of the podocyte-expressed transcription factor Tcf21/Pod1 results in podocyte differentiation defects and FSGS.

Podocytes are terminally differentiated cells with an elaborate cytoskeleton and are critical components of the glomerular barrier. We identified a bHLH transcription factor, Tcf21, that is highly expressed in developing and mature podocytes. Because conventional Tcf21 knockout mice die in the perinatal period with major cardiopulmonary defects, we generated a conditional Tcf21 knockout mouse to explore the role of this transcription factor in podocytes in vivo.

Topical application of ex vivo expanded endothelial progenitor cells promotes vascularisation and wound healing in diabetic mice.

Impaired wound healing leading to skin ulceration is a serious complication of diabetes and may be caused by defective angiogenesis. Endothelial progenitor cells (EPCs) can augment neovascularisation in the ischaemic tissue. Experiments were performed to test the hypothesis that locally administered EPCs can promote wound healing in diabetes.

Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein.

Both estradiol (E2) and Sonic Hedgehog (Shh) contribute to angiogenesis and nerve regeneration. Here, we investigated whether E2 improves the recovery of injured nerves by downregulating the Shh inhibitor hedgehog-interacting protein (HIP) and increasing Shh-induced angiogenesis. Mice were treated with local injections of E2 or placebo one week before nerve-crush injury; 28 days after injury, nerve conduction velocity, exercise duration, and vascularity were significantly greater in E2-treated mice than in placebo-treated mice.

Angiographic and magnetic resonance imaging evaluation of in-hospital delay in primary percutaneous intervention delivery on myocardial salvage.

Shortening symptom-to-reperfusion time improves prognosis in patients with ST-segment elevation myocardial infarction. Accordingly, current guidelines target a door-to-balloon time <90 minutes, irrespective of symptom-to-door time; nevertheless, the relation between door-to-balloon and symptom-to-door time and its potential impact on myocardial salvage remains largely unknown. We investigated the influence of door-to-balloon guideline fulfillment on myocardial salvage in patients presenting with different symptom-to-door times.

Determinants of myocardial salvage during acute myocardial infarction: evaluation with a combined angiographic and CMR myocardial salvage index.

Objectives: This study examined the contribution of symptom-to-reperfusion time, collateral flow, and antegrade flow in the infarct-related artery on myocardial salvage using a combined angiographic-cardiac magnetic resonance (CMR) method.

Background: The myocardium supplied by an acutely occluded artery defines the anatomical area at risk for infarction. This area can be determined independently of residual coronary flow to the risk region.

Correspondence between the 17-segment model and coronary arterial anatomy using contrast-enhanced cardiac magnetic resonance imaging.

Objectives: The purpose of this study was to investigate the correspondence between the coronary arterial anatomy and supplied myocardium based on the proposed American Heart Association 17-segment model.

Background: Standardized assignment of coronary arteries to specific myocardial segments is currently based on empirical assumptions.

Methods: A cardiac magnetic resonance study was performed in 93 subjects following acute myocardial infarction treated with primary percutaneous coronary intervention.

Frequency gradients during two different forms of fibrillation in the canine atria.

Background: Atrial fibrillation (AF) is thought to be sustained by multiple reentrant wavelets or firing foci.

Objective: The aim of this study was to compare the spectral domain characteristics in the left atrium (LA) and right atrium (RA) in two different models of AF.

Methods: Rectangular 8 x 14 electrode arrays were placed on the LA and RA of 14 anesthetized dogs.

Characterization of fibrillatory rhythms by ensemble vector directional analysis.

Recent studies have demonstrated that fibrillatory rhythms are not random phenomena but have definable patterns. However, standard mapping techniques may have limitations in their ability to identify the organization of fibrillation. The purpose of this study was to develop and apply a method, "ensemble vector mapping," for characterizing the spatiotemporal organization of fibrillation.

In vitro performance characteristics of reused ablation catheters.

Background: Prior studies have found that there is a widespread practice of catheter reprocessing in cardiac electrophysiology laboratories. Effects of reprocessing of ablation catheters on temperature sensing and mechanical deflection are not fully known.

Methods: Twenty-four new and used ablation catheters were studied.

TrueFISP: assessment of accuracy for measurement of left ventricular mass in an animal model.

Purpose: To test the accuracy of a high performance true fast imaging with steady-state precession (TrueFISP) pulse sequence for the assessment of left ventricular (LV) mass in a large animal model on 1.5-T scanners.

Materials And Methods: We imaged dogs (N = 10) on a clinical 1.