The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer's disease.

Introduction: The disintegrin and metalloproteinase 17 (ADAM17) exhibits α-secretase activity, whereby it can prevent the production of neurotoxic amyloid precursor protein-α (APP). ADAM17 is abundantly expressed in vascular endothelial cells and may act to regulate vascular homeostatic responses, including vasomotor function, vascular wall morphology, and formation of new blood vessels. The role of vascular ADAM17 in neurodegenerative diseases remains poorly understood.

Manganese-enhanced magnetic resonance imaging method detects age-related impairments in axonal transport in mice and attenuation of the impairments by a microtubule-stabilizing compound.

In this study a manganese-enhanced magnetic resonance imaging (MEMRI) method was developed for mice for measuring axonal transport (AXT) rates in real time in olfactory receptor neurons, which project from the olfactory epithelium to the olfactory neuronal layer of the olfactory bulb. Using this MEMRI method, two major experiments were conducted: 1) an evaluation of the effects of age on AXT rates and 2) an evaluation of the brain-penetrant, microtubule-stabilizing agent, Epothilone D for effect on AXT rates in aged mice. In these studies, we improved upon previous MEMRI approaches to develop a method where real-time measurements (32 time points) of AXT rates in mice can be determined over a single (approximately 100 min) scanning session.

Review: Circadian clocks and rhythms in the vascular tree.

The progression of vascular disease is influenced by many factors including aging, gender, diet, hypertension, and poor sleep. The intrinsic vascular circadian clock and the timing it imparts on the vasculature both conditions and is conditioned by all these variables. Circadian rhythms and their molecular components are rhythmically cycling in each endothelial cell, smooth muscle cell, in each artery, arteriole, vein, venule, and capillary.

Guidelines for the design and conduct of human clinical trials on ingestion-time differences - chronopharmacology and chronotherapy - of hypertension medications.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e.

Old and New Roles and Evolving Complexities of Cardiovascular Clocks.

The cardiovascular (CV) system has been established to be significantly influenced by the molecular components of circadian rhythm. Oscillations of circadian rhythm occur within the circulation to affect thrombosis and blood pressure and within CV tissues including arteries, heart, and kidney to control function. Physiologic and molecular oscillations of circadian rhythm have been well connected via global, tissue-specific, and transgenic reporter mouse models of key core clock signals such as , , and which can produce both pathology and protection with their mutation.

Galectin-3: A Harbinger of Reactive Oxygen Species, Fibrosis, and Inflammation in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease arising from the narrowing of pulmonary arteries (PAs) resulting in high pulmonary arterial blood pressure and ultimately right ventricle (RV) failure. A defining characteristic of PAH is the excessive and unrelenting inward remodeling of PAs that includes increased proliferation, inflammation, and fibrosis. There is no cure for PAH nor interventions that effectively arrest or reverse PA remodeling, and intensive research over the past several decades has sought to identify novel molecular mechanisms of therapeutic value.

Increased arterial pressure in mice with overexpression of the ADHD candidate gene calcyon in forebrain.

The link between blood pressure (BP) and cerebral function is well established. However, it is not clear whether a common mechanism could underlie the relationship between elevated BP and cognitive deficits. The expression of calcyon, a gene abundant in catecholaminergic and hypothalamic nuclei along with other forebrain regions, is increased in the brain of the spontaneously hypertensive rat (SHR) which is a widely accepted animal model of essential hypertension and attention deficit hyperactivity disorder (ADHD).

Immunohistochemistry of the circadian clock in mouse and human vascular tissues.

Aim: The circadian clock is a molecular network that controls the body physiological rhythms. In blood vessels, the circadian clock components modulate vascular remodeling, blood pressure, and signaling. The goal in this study was to determine the pattern of expression of circadian clock proteins in the endothelium, smooth muscle, and adventitia of the vasculature of human and mouse tissues.

Hsp70 Suppresses Mitochondrial Reactive Oxygen Species and Preserves Pulmonary Microvascular Barrier Integrity Following Exposure to Bacterial Toxins.

Pneumonia is a leading cause of death in children and the elderly worldwide, accounting for 15% of all deaths of children under 5 years old. is a common and aggressive cause of pneumonia and can also contribute to meningitis and sepsis. Despite the widespread use of antibiotics, mortality rates for pneumonia remain unacceptably high in part due to the release of bacterial toxins.

Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction.

Objective: A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity.

Approach And Results: Coronary arterioles (CAs, ≈90 µm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.

Differential Regulation of BMAL1, CLOCK, and Endothelial Signaling in the Aortic Arch and Ligated Common Carotid Artery.

The circadian clock is rhythmically expressed in blood vessels, but the interaction between the circadian clock and disturbed blood flow remains unclear. We examined the relationships between BMAL1 and CLOCK and 2 regulators of endothelial function, AKT1 and endothelial nitric oxide synthase (eNOS), in vascular regions of altered blood flow. We found that the aortic arch from WT mice exhibited reduced sensitivity to acetylcholine (Ach)-mediated relaxation relative to the thoracic aorta.

Endotoxin Disrupts Circadian Rhythms in Macrophages via Reactive Oxygen Species.

The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior.

Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice.

Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.

Objective: Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value.

Opposing actions of heat shock protein 90 and 70 regulate nicotinamide adenine dinucleotide phosphate oxidase stability and reactive oxygen species production.

Objective: Excessive reactive oxygen species contribute to vascular dysfunction. We have previously shown that heat shock protein (Hsp90) inhibitors potently suppress Nox 1 to 3 and 5, and the goals of this study were to identify how molecular chaperones regulate Nox function.

Methods And Results: In vitro, protein expression of Nox 1 to 2, 5 was decreased by Hsp90 inhibitors in multiple cell types (human pulmonary artery endothelial cells, neutrophils, macrophages, and human saphenous vein).

Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice.

Rationale: Disruption of the circadian clock in mice produces vascular dysfunction as evidenced by impairments in endothelium-dependent signaling, vasomotion, and blood vessel remodeling. Although the altered function of endothelial NO synthase and the overproduction of reactive oxygen species are central to dysfunction of the endothelium, to date, the impact of the circadian clock on endothelial NO synthase coupling and vascular reactive oxygen species production is not known.

Objective: The goals of the present study were to determine whether deletion of a critical component of the circadian clock, Bmal1, can influence endothelial NO synthase coupling and reactive oxygen species levels in arteries from Bmal1-knockout (KO) mice.

Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels.

The expression and functional significance of NADPH oxidase 5 (Nox5) and its five isoforms in vascular cells is poorly understood. The goal of this study was to determine whether Nox5-α, -β, -δ, -γ, and -ε (short) are expressed in human blood vessels and evaluate their respective functions. Nox5 mRNA and protein were detected in human blood vessels, cultured human vascular smooth muscle (HVSMC) and endothelium, but not fibroblasts.

Endothelium derived nitric oxide synthase negatively regulates the PDGF-survivin pathway during flow-dependent vascular remodeling.

Chronic alterations in blood flow initiate structural changes in vessel lumen caliber to normalize shear stress. The loss of endothelial derived nitric oxide synthase (eNOS) in mice promotes abnormal flow dependent vascular remodeling, thus uncoupling mechanotransduction from adaptive vascular remodeling. However, the mechanisms of how the loss of eNOS promotes abnormal remodeling are not known.

Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis.

The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant.

SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases.

Objective: Increased protein SUMOylation (small ubiquitin-related modifier [SUMO]) provides protection from cellular stress, including oxidative stress, but the mechanisms involved are incompletely understood. The NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS) and oxidative stress, and thus our goal was to determine whether SUMO regulates NADPH oxidase activity.

Methods And Results: Increased expression of SUMO1 potently inhibited the activity of Nox1 to Nox5.

Matrix metalloproteinase 2 and 9 dysfunction underlie vascular stiffness in circadian clock mutant mice.

Objective: To determine if elasticity in blood vessels is compromised in circadian clock-mutant mice (Bmal1-knockout [KO] and Per-triple KO) and if matrix metalloproteinases (MMPs) might confer these changes in compliance.

Methods And Results: High-resolution ultrasonography in vivo revealed impaired remodeling and increased pulse-wave velocity in the arteries of Bmal1-KO and Per-triple KO mice. In addition, compliance of remodeled arteries and naïve pressurized arterioles ex vivo from Bmal1-KO and Per-triple KO mice was reduced, consistent with stiffening of the vascular bed.