HO Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling.

In diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen peroxide (HO) formation to compensate for NO deficiency. This hypothesis was tested in coronary arterioles isolated from pigs with 2-week diabetes after streptozocin injection.

Intravitreal Administration of Stanniocalcin-1 Rescues Photoreceptor Degeneration with Reduced Oxidative Stress and Inflammation in a Porcine Model of Retinitis Pigmentosa.

Purpose: To investigate the effect of stanniocalcin-1 (STC-1), a secreted polypeptide exhibiting multiple functions in cell survival and death, on photoreceptor degeneration in a porcine model of retinitis pigmentosa (RP).

Methods: P23H transgenic pigs (TG P23H) and wild-type hybrid littermates were obtained from the National Swine Resource and Research Center. Human recombinant STC-1 was injected intravitreally every 2 weeks from postnatal day 15 (P15) to P75.

Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation.

Protein kinase C (PKC) activation can evoke vasoconstriction and contribute to coronary disease. However, it is unclear whether PKC activation, without activating the contractile machinery, can lead to coronary arteriolar dysfunction. The vasoconstriction induced by the PKC activator phorbol 12,13-dibutyrate (PDBu) was examined in isolated porcine coronary arterioles.

Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice.

We investigated and compared the susceptibility of retinal blood flow regulation and neural function in mice developing type 2 diabetes. The longitudinal changes in retinal neuronal function and blood flow responses to a 10-min systemic hyperoxia and a 3-min flicker stimulation were evaluated every 2 weeks in diabetic db/db mice and nondiabetic controls (db/m) from age 8 to 20 weeks. The retinal blood flow and neural activity were assessed using laser speckle flowgraphy and electroretinography (ERG), respectively.

Contributions of Sodium-Hydrogen Exchanger 1 and Mitogen-Activated Protein Kinases to Enhanced Retinal Venular Constriction to Endothelin-1 in Diabetes.

Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1-induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules.

Visualization of Retinal Blood Vessels.

The retina offers a unique opportunity to directly visualize blood vessels in vivo noninvasively. Over the past few decades, several new imaging techniques have been adapted to study the retinal vasculature in the laboratory in animal models and in the clinic in human subjects. High-contrast, finely detailed fundus images can be acquired by confocal scanning laser ophthalmoscopy (cSLO).

Laser-Induced Choroidal Neovascularization in Rats.

The laser-induced choroidal neovascularization (CNV) model has been widely used for research on wet age-related macular degeneration (wet-AMD) and other ocular neovascular diseases. In this model, the Bruch membrane is perforated by laser injury, resulting in neovascularization formed from the choroidal capillaries. It has become a standard method to evaluate the effect of different treatments on CNV progression in preclinical studies.

Longitudinal stability of retinal blood flow regulation in response to flicker stimulation and systemic hyperoxia in mice assessed with laser speckle flowgraphy.

This study aimed to evaluate longitudinal changes in retinal blood flow in response to flicker stimulation and systemic hyperoxia in mice using a laser speckle flowgraphy (LSFG-Micro). The retinal blood flow in vascular area surrounding the optic nerve head was measured in 8-week-old male mice every 2 weeks until age 20-week. The coefficient of variation of retinal blood flow under resting condition was analyzed every 2 weeks to validate the consistency of the measurement.

Hyperglycemia Augments Endothelin-1-Induced Constriction of Human Retinal Venules.

Purpose: Endothelin-1 (ET-1) is a potent vasoactive factor implicated in development of diabetic retinopathy, which is commonly associated with retinal edema and hyperglycemia. Although the vasomotor activity of venules contributes to the regulation of tissue fluid homeostasis, responses of human retinal venules to ET-1 under euglycemia and hyperglycemia remain unknown and the ET-1 receptor subtype corresponding to vasomotor function has not been determined. Herein, we addressed these issues by examining the reactivity of isolated human retinal venules to ET-1, and results from porcine retinal venules were compared.

Role of Arginase in Selective Impairment of Endothelium-Dependent Nitric Oxide Synthase-Mediated Dilation of Retinal Arterioles during Early Diabetes.

Purpose: Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation.

Newly Identified Peptide, Peptide Lv, Promotes Pathological Angiogenesis.

Background We recently discovered a small endogenous peptide, peptide Lv, with the ability to activate vascular endothelial growth factor receptor 2 and its downstream signaling. As vascular endothelial growth factor through vascular endothelial growth factor receptor 2 contributes to normal development, vasodilation, angiogenesis, and pathogenesis of various diseases, we investigated the role of peptide Lv in vasodilation and developmental and pathological angiogenesis in this study. Methods and Results The endothelial cell proliferation, migration, and 3-dimensional sprouting assays were used to test the abilities of peptide Lv in angiogenesis in vitro.

Hyperglycemia Enhances Constriction of Retinal Venules via Activation of the Reverse-Mode Sodium-Calcium Exchanger.

Diabetes is associated with hyperglycemia and impairment of retinal microvascular function. However, the impact of hyperglycemia on retinal venular constriction remains unknown. We examined retinal venular responsiveness to endogenous vasoconstrictors and the contribution of the reverse-mode sodium-calcium exchanger (NCX) to these responses during hyperglycemia.

Requisite roles of LOX-1, JNK, and arginase in diabetes-induced endothelial vasodilator dysfunction of porcine coronary arterioles.

Diabetes is associated with cardiac inflammation and impaired endothelium-dependent coronary vasodilation, but molecular mechanisms involved in this dysfunction remain unclear. We examined contributions of inflammatory molecules lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), stress-activated kinases (c-Jun N-terminal kinase [JNK] and p38), arginase, and reactive oxygen species to coronary arteriolar dysfunction in a porcine model of type 1 diabetes. Coronary arterioles were isolated from streptozocin-induced diabetic pigs and control pigs for vasoreactivity and molecular/biochemical studies.

Data on SD-OCT image acquisition, ultrastructural features, and horizontal tissue shrinkage in the porcine retina.

The data presented in this article are related to the research paper entitled "Correlation of Spectral Domain Optical Coherence Tomography with Histology and Electron Microscopy in the Porcine Retina" (Xie et al., 2018) [2]. This research data highlights our technique for retinal fundus image acquisition during spectral domain optical coherence tomography (SD-OCT) in a large animal model.

Constriction of Retinal Venules to Endothelin-1: Obligatory Roles of ETA Receptors, Extracellular Calcium Entry, and Rho Kinase.

Purpose: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in retinal venous pathologies such as diabetic retinopathy and retinal vein occlusion. However, underlying mechanisms contributing to venular constriction remain unknown. Thus, we examined the roles of ET-1 receptors, extracellular calcium (Ca2+), L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) in ET-1-induced constriction of retinal venules.

Correlation of spectral domain optical coherence tomography with histology and electron microscopy in the porcine retina.

Spectral domain optical coherence tomography (SD-OCT) is used as a non-invasive tool for retinal morphological assessment in vivo. Information on the correlation of SD-OCT with retinal histology in the porcine retina, a model resembling the human retina, is limited. Herein, we correlated the hypo- and hyper-reflective bands on SD-OCT with histology of the lamellar architecture and cellular constituents of the porcine retina.

Intravitreal Stanniocalcin-1 Enhances New Blood Vessel Growth in a Rat Model of Laser-Induced Choroidal Neovascularization.

Purpose: The purpose of this study was to investigate the impact of stanniocalcin-1 (STC-1), a photoreceptor-protective glycoprotein, on the development of choroidal neovascularization (CNV) in relation to VEGF and its main receptor (VEGFR2) expression after laser injury.

Methods: In rats, CNV was induced by laser photocoagulation in both eyes, followed by intravitreal injection of STC-1 in the right eye and vehicle or denatured STC-1 injection in the left eye as control. Two weeks after laser injury, fundus autofluorescence (FAF) imaging and fundus fluorescein angiography (FFA) were performed.

Alterations of Ocular Hemodynamics Impair Ophthalmic Vascular and Neuroretinal Function.

Hypertension is associated with numerous diseases, but its direct impact on the ocular circulation and neuroretinal function remains unclear. Herein, mouse eyes were challenged with different levels of hemodynamic insult via transverse aortic coarctation, which increased blood pressure and flow velocity by 50% and 40%, respectively, in the right common carotid artery, and reduced those parameters by 30% and 40%, respectively, in the left common carotid artery. Blood velocity in the right central retinal artery gradually increased up to 40% at 4 weeks of transverse aortic coarctation, and the velocity in the left central retinal artery gradually decreased by 20%.

Enhanced endothelin-1/Rho-kinase signalling and coronary microvascular dysfunction in hypertensive myocardial hypertrophy.

Aims: Hypertensive cardiac hypertrophy is associated with reduced coronary flow reserve, but its impact on coronary flow regulation and vasomotor function remains incompletely understood and requires further investigation.

Methods And Results: Left ventricular hypertrophy was induced in mice by transverse aortic coarctation (TAC) for 4 weeks. The left coronary artery blood velocity (LCABV) and myocardium lactate level were measured following the metabolic activation by isoproterenol.

Histamine-Induced Dilation of Isolated Porcine Retinal Arterioles: Role of Endothelium-Derived Hyperpolarizing Factor.

Purpose: Although endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles has been well described, the role of endothelium-derived hyperpolarizing factor (EDHF) in the retinal arteriolar response remains unclear. In the current study, we examined the contribution of EDHF to the retinal arteriolar dilation to the inflammatory agent histamine and investigated the signaling mechanisms underlying this vasomotor activity.

Methods: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow for functional study by using video microscopic techniques.

Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles.

Purpose: Hyperglycemia, a hallmark of diabetes mellitus, is associated with retinal inflammation and impairment of endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles. However, molecular mechanisms involved in this diminished endothelial vasodilator function remain unclear. We examined whether inflammatory stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38, contribute to retinal arteriolar dysfunction during exposure to acute and chronic hyperglycemia.

Safety and toxicity of nanomaterials for ocular drug delivery applications.

Multifunctional nanomaterials are rapidly emerging for ophthalmic delivery of therapeutics to facilitate safe and effective targeting with improved patient compliance. Because of their extremely high area to volume ratio, nanomaterials often have physicochemical properties that are different from those of their larger counterparts. There exists a complex relationship between the physicochemical properties (composition, size, shape, charge, roughness, and porosity) of the nanomaterials and their interaction with the biological system.

VEGF Receptor-2-Linked PI3K/Calpain/SIRT1 Activation Mediates Retinal Arteriolar Dilations to VEGF and Shear Stress.

Purpose: Vasomotor responses of retinal arterioles to luminal flow/shear stress and VEGF have a critical role in governing retinal blood flow possibly via nitric oxide synthase (NOS) activation. However, the cellular mechanism for flow-sensitive vasomotor activity in relation to VEGF signaling in retinal arterioles has not been characterized. We used an isolated vessel approach to specifically address this issue.

Endothelin-1 impairs coronary arteriolar dilation: Role of p38 kinase-mediated superoxide production from NADPH oxidase.

Elevated levels of endothelin-1 (ET-1), a potent vasoactive peptide, are implicated as a risk factor for cardiovascular diseases by exerting vasoconstriction. The aim of this study was to address whether ET-1, at sub-vasomotor concentrations, elicits adverse effects on coronary microvascular function. Porcine coronary arterioles (50-100μm) were isolated, cannulated and pressurized without flow for in vitro study.

Stromal interaction molecule 1 (STIM1) and Orai1 mediate histamine-evoked calcium entry and nuclear factor of activated T-cells (NFAT) signaling in human umbilical vein endothelial cells.

Histamine is an important immunomodulator involved in allergic reactions and inflammatory responses. In endothelial cells, histamine induces Ca(2+) mobilization by releasing Ca(2+) from the endoplasmic reticulum and eliciting Ca(2+) entry across the plasma membrane. Herein, we show that histamine-evoked Ca(2+) entry in human umbilical vein endothelial cells (HUVECs) is sensitive to blockers of Ca(2+) release-activated Ca(2+) (CRAC) channels.