To describe the clinical features of a unique pigmentary maculopathy noted in the setting of chronic exposure to pentosan polysulfate sodium (PPS), a therapy for interstitial cystitis (IC).
...Retrospective case series.
Six adult patients evaluated by a single clinician between May 1, 2015, and October 1, 2017.
Patients were identified by query of the electronic medical record system. Local records were reviewed, including results of the clinical examination, retinal imaging, and visual function assessment with static perimetry and electroretinography. Molecular testing assessed for known macular dystrophy and mitochondrial cytopathy genotypes.
Mean best-corrected visual acuity (BCVA; in logarithm of the minimum angle of resolution units), median cumulative PPS exposure, subjective nature of the associated visual disturbance, qualitative examination and imaging features, and molecular testing results.
The median age at presentation was 60 years (range, 37-62 years). All patients received PPS for a diagnosis of IC, with a median cumulative exposure of 2263 g (range, 1314-2774 g), over a median duration of exposure of 186 months (range, 144-240 months). Most patients (4 of 6) reported difficulty reading as the most bothersome symptom. Mean BCVA was 0.1±0.18 logarithm of the minimum angle of resolution. On fundus examination, nearly all eyes showed subtle paracentral hyperpigmentation at the level of the retinal pigment epithelium (RPE) with a surrounding array of vitelliform-like deposits. Four eyes of 2 patients showed paracentral RPE atrophy, and no eyes demonstrated choroidal neovascularization. Multimodal retinal imaging demonstrated abnormality of the RPE generally contained in a well-delineated area in the posterior pole. None of the 4 patients who underwent molecular testing of nuclear DNA returned a pathogenic mutation. Additionally, all 6 patients showed negative results for pathogenic variants in the mitochondrial gene MTTL1.
We describe a novel and possibly avoidable maculopathy associated with chronic exposure to PPS. Patients reported symptoms of difficulty reading and prolonged dark adaptation despite generally intact visual acuity and subtle funduscopic findings. Multimodal imaging and functional studies are suggestive of a primary RPE injury. Additional investigation is warranted to explore causality further.
Smooth muscle cells transition reversibly between contractile and noncontractile phenotypes in response to diverse influences, including many from mitochondria. Numerous molecules including ...myocardin, procontractile miRNAs, and the mitochondrial protein prohibitin-2 promote contractile differentiation; this is opposed by mitochondrial reactive oxygen species (mtROS), high lactate concentrations, and metabolic reprogramming induced by mitophagy and/or mitochondrial fission. A major pathway through which vascular pathologies such as oncogenic transformation, pulmonary hypertension, and atherosclerosis cause loss of vascular contractility is by enhancing mitophagy and mitochondrial fission with secondary effects on smooth muscle phenotype. Proproliferative miRNAs and the mitochondrial translocase TOMM40 also attenuate contractile differentiation. Hypoxia can initiate loss of contractility by enhancing mtROS and lactate production while simultaneously depressing mitochondrial respiration. Mitochondria can reduce cytosolic calcium by moving it across the inner mitochondrial membrane via the mitochondrial calcium uniporter, and then through mitochondria-associated membranes to and from calcium stores in the sarcoplasmic/endoplasmic reticulum. Through these effects on calcium, mitochondria can influence multiple calcium-sensitive nuclear transcription factors and genes, some of which govern smooth muscle phenotype, and possibly also the production of genomically encoded mitochondrial proteins and miRNAs (mitoMirs) that target the mitochondria. In turn, mitochondria also can influence nuclear transcription and mRNA processing through mitochondrial retrograde signaling, which is currently a topic of intensive investigation. Mitochondria also can signal to adjacent cells by contributing to the content of exosomes. Considering these and other mechanisms, it is becoming increasingly clear that mitochondria contribute significantly to the regulation of smooth muscle phenotype and differentiation.
MicroRNAs (miRNAs) are a class of highly conserved non-coding RNAs with 21-25 nucleotides in length and play an important role in regulating gene expression at the posttranscriptional level via ...base-paring with complementary sequences of the 3'-untranslated region of the target gene mRNA, leading to either transcript degradation or translation inhibition. Brain-enriched miRNAs act as versatile regulators of brain development and function, including neural lineage and subtype determination, neurogenesis, synapse formation and plasticity, neural stem cell proliferation and differentiation, and responses to insults. Herein, we summarize the current knowledge regarding the role of miRNAs in brain development and cerebrovascular pathophysiology. We review recent progress of the miRNA-based mechanisms in neuronal and cerebrovascular development as well as their role in hypoxic-ischemic brain injury. These findings hold great promise, not just for deeper understanding of basic brain biology but also for building new therapeutic strategies for prevention and treatment of pathologies such as cerebral ischemia.
Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving ...complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.
The human cerebral vasculature originates in the fourth week of gestation and continues to expand and diversify well into the first few years of postnatal life. A key feature of this growth is smooth ...muscle differentiation, whereby smooth muscle cells within cerebral arteries transform from migratory to proliferative to synthetic and finally to contractile phenotypes. These phenotypic transformations can be reversed by pathophysiological perturbations such as hypoxia, which causes loss of contractile capacity in immature cerebral arteries. In turn, loss of contractility affects all whole-brain cerebrovascular responses, including those involved in flow-metabolism coupling, vasodilatory responses to acute hypoxia and hypercapnia, cerebral autoregulation, and reactivity to activation of perivascular nerves. Future strategies to minimize cerebral injury following hypoxia-ischemic insults in the immature brain might benefit by targeting treatments to preserve and promote contractile differentiation in the fetal cerebrovasculature. This could potentially be achieved through inhibition of receptor tyrosine kinase-mediated growth factors, such as vascular endothelial growth factor and platelet-derived growth factor, which are mobilized by hypoxic and ischemic injury and which facilitate contractile dedifferentiation. Interruption of the effects of other vascular mitogens, such as endothelin and angiotensin-II, and even some miRNA species, also could be beneficial. Future experimental work that addresses these possibilities offers promise to improve current clinical management of neonates who have suffered and survived hypoxic, ischemic, asphyxic, or inflammatory cerebrovascular insults.
Peace expresses insights on the cardiac function of hHS-M21, a heart-specific small subunit of myosin light chain phosphatases (MLCP) which facilitate the targeting of Rho-associated coiled-coil ...forming kinase (ROCK). He explores the study by Arimura et al which involve the creation of multiple lines of transgenic mice which exhibited cardiac specific overexpression of the subunit which according to him can cause multiple indications of contractile dysfunction including sinus bradycardia and atrioventricular conduction disturbances. He also cited that the key finding in the study was the overall phosphorylation of MLC2 was not altered in mice despite the increase in myofilament calcium sensitivity.
The concept of the neurovascular unit as the key brain component affected by stroke is controversial, because current definitions of this entity neglect mechanisms that control perfusion and ...reperfusion of arteries and arterioles upstream of the cerebral microcirculation. Indeed, although definitions vary, many researchers consider the neurovascular unit to be restricted to endothelial cells, neurons and glia within millimetres of the cerebral capillary microcirculation. This Perspectives article highlights the roles of vascular smooth muscle, endothelial cells and perivascular innervation of cerebral arteries in the initiation and progression of, and recovery from, ischaemic stroke. The concept of the vascular neural network-which includes cerebral arteries, arterioles, and downstream neuronal and glial cell types and structures-is introduced as the fundamental component affected by stroke pathophysiology. The authors also propose that the vascular neural network should be considered the main target for future therapeutic intervention after cerebrovascular insult.
Departments of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California
Fetal cerebrovascular responses to acute ...hypoxia are fundamentally different from those observed in the adult cerebral circulation. The magnitude of hypoxic vasodilatation in the fetal brain increases with postnatal age although fetal cerebrovascular responses to acute hypoxia can be complicated by age-dependent depressions of blood pressure and ventilation. Acute hypoxia promotes adenosine release, which depresses fetal cerebral oxygen consumption through action of adenosine on neuronal A 1 receptors and vasodilatation through activation of A 2 receptors on cerebral arteries. The vascular effect of adenosine can account for approximately half the vasodilatation observed in response to hypoxia. Hypoxia-induced release of nitric oxide and opioids can account for much of the adenosine-independent cerebral vasodilatation observed in response to hypoxia in the fetus. Direct effects of hypoxia on cerebral arteries account for the remaining fraction, although the vascular endothelium contributes relatively little to hypoxic vasodilatation in the immature cerebral circulation. In contrast to acute hypoxia, fetal cerebral blood flow tends to normalize during acclimatization to chronic hypoxia even though cardiac output is depressed. However, uncompensated chronic hypoxia in the fetus can produce significant changes in brain structure and function, alteration of respiratory drive and fluid balance, and increased incidence of intracranial hemorrhage and periventricular leukomalacia. At the level of the fetal cerebral arteries, chronic hypoxia increases protein content and depresses norepinephrine release, contractility, and receptor densities associated with contraction but also attenuates endothelial vasodilator capacity and decreases the ability of ATP-sensitive and calcium-sensitive potassium channels to promote vasorelaxation. Overall, fetal cerebrovascular adaptations to chronic hypoxia appear prioritized to conserve energy while preserving basic contractility. Many gaps remain in our understanding of how the effects of acute and chronic hypoxia are mediated in fetal cerebral arteries, but studies of adult cerebral arteries have produced many powerful pharmacological and molecular tools that are simply awaiting application in studies of fetal cerebral artery responses to hypoxia.
cerebral arteries; neonate; high altitude; perivascular innervation; vascular endothelium
Address for reprint requests and other correspondence: W. J. Pearce, Center for Perinatal Biology, Loma Linda Univ. School of Medicine, Loma Linda, CA 92350 (e-mail: wpearce{at}llu.edu )
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