Retinal Vasculature in Development and Diseases

The retina is one of the most metabolically active tissues in the body, consuming high levels of oxygen and nutrients. A well-organized ocular vascular system adapts to meet the metabolic requirements of the retina to ensure visual function. Pathological conditions affect growth of the blood vessels in the eye. Understanding the neuronal biological processes that govern retinal vascular development is of interest for translational researchers and clinicians to develop preventive and interventional therapeutics for vascular eye diseases that address early drivers of abnormal vascular growth. This review summarizes the current knowledge of the cellular and molecular processes governing both physiological and pathological retinal vascular development, which is dependent on the interaction among retinal cell populations, including neurons, glia, immune cells, and vascular endothelial cells. We also review animal models currently used for studying retinal vascular development.

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Viral Bad News Sent by EVAIL

Viruses ◽

10.3390/v13061168 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1168

Author(s):

Matthias Clauss ◽

Sarvesh Chelvanambi ◽

Christine Cook ◽

Rabab ElMergawy ◽

Navneet Dhillon

Keyword(s):

Host Response ◽

Vascular Endothelial Cells ◽

Current Knowledge ◽

Alternative Pathway ◽

Vascular Endothelial Cell ◽

Extracellular Vesicle ◽

Cardiovascular Complications ◽

The Body ◽

Vascular Endothelial ◽

Cardiovascular Pathologies

This article reviews the current knowledge on how viruses may utilize Extracellular Vesicle Assisted Inflammatory Load (EVAIL) to exert pathologic activities. Viruses are classically considered to exert their pathologic actions through acute or chronic infection followed by the host response. This host response causes the release of cytokines leading to vascular endothelial cell dysfunction and cardiovascular complications. However, viruses may employ an alternative pathway to soluble cytokine-induced pathologies—by initiating the release of extracellular vesicles (EVs), including exosomes. The best-understood example of this alternative pathway is human immunodeficiency virus (HIV)-elicited EVs and their propensity to harm vascular endothelial cells. Specifically, an HIV-encoded accessory protein called the “negative factor” (Nef) was demonstrated in EVs from the body fluids of HIV patients on successful combined antiretroviral therapy (ART); it was also demonstrated to be sufficient in inducing endothelial and cardiovascular dysfunction. This review will highlight HIV-Nef as an example of how HIV can produce EVs loaded with proinflammatory cargo to disseminate cardiovascular pathologies. It will further discuss whether EV production can explain SARS-CoV-2-mediated pulmonary and cardiovascular pathologies.

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Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development

International Journal of Molecular Sciences ◽

10.3390/ijms22062804 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2804

Author(s):

Yasuo Yoshitomi ◽

Takayuki Ikeda ◽

Hidehito Saito-Takatsuji ◽

Hideto Yonekura

Keyword(s):

Endothelial Cells ◽

Transcription Factor ◽

Blood Vessel ◽

Vascular Endothelial Cells ◽

Vascular Development ◽

Endothelial Cell Migration ◽

Vascular Endothelial ◽

Blood Vessel Formation ◽

Vessel Formation

Blood vessels are essential for the formation and maintenance of almost all functional tissues. They play fundamental roles in the supply of oxygen and nutrition, as well as development and morphogenesis. Vascular endothelial cells are the main factor in blood vessel formation. Recently, research findings showed heterogeneity in vascular endothelial cells in different tissue/organs. Endothelial cells alter their gene expressions depending on their cell fate or angiogenic states of vascular development in normal and pathological processes. Studies on gene regulation in endothelial cells demonstrated that the activator protein 1 (AP-1) transcription factors are implicated in angiogenesis and vascular development. In particular, it has been revealed that JunB (a member of the AP-1 transcription factor family) is transiently induced in endothelial cells at the angiogenic frontier and controls them on tip cells specification during vascular development. Moreover, JunB plays a role in tissue-specific vascular maturation processes during neurovascular interaction in mouse embryonic skin and retina vasculatures. Thus, JunB appears to be a new angiogenic factor that induces endothelial cell migration and sprouting particularly in neurovascular interaction during vascular development. In this review, we discuss the recently identified role of JunB in endothelial cells and blood vessel formation.

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Biomechanical interactions of Schistosoma mansoni eggs with vascular endothelial cells facilitate egg extravasation

10.1101/2021.09.16.459846 ◽

2021 ◽

Author(s):

Yi-Ting Yeh ◽

Danielle E. Skinner ◽

Ernesto Criado-Hidalgo ◽

Natalie Shee Chen ◽

Antoni Garcia-De Herreros ◽

...

Keyword(s):

Endothelial Cells ◽

Schistosoma Mansoni ◽

Disease Transmission ◽

Vascular Endothelial Cells ◽

Flexible Substrate ◽

Blood Stream ◽

The Body ◽

Dependent Manner ◽

Vascular Endothelial ◽

Maturation State

AbstractThe eggs of the parasitic blood fluke, Schistosoma, are the main drivers of the chronic pathologies associated with schistosomiasis, a disease of poverty afflicting approximately 220 million people worldwide. Eggs laid by Schistosoma mansoni in the bloodstream of the host are encapsulated by vascular endothelial cells (VECs), the first step in the migration of the egg from the blood stream into the lumen of the gut and eventual exit from the body. The biomechanics associated with encapsulation and extravasation of the egg are poorly understood. We demonstrate that S. mansoni eggs induce VECs to form two types of membrane extensions during encapsulation; filopodia that probe eggshell surfaces and intercellular nanotubes that presumably facilitate VEC communication. Encapsulation efficiency, the number of filopodia and intercellular nanotubes, and the length of these structures depend on the egg’s vitality and, to a lesser degree, its maturation state. During encapsulation, live eggs induce VEC contractility and membranous structures formation, in a Rho/ROCK pathway-dependent manner. Using elastic hydrogels embedded with fluorescent microbeads as substrates to culture VECs, live eggs induce VECs to exert significantly greater contractile forces during encapsulation than dead eggs, which leads to 3D deformations on both the VEC monolayer and the flexible substrate underneath. These significant mechanical deformations cause the VEC monolayer tension to fluctuate with eventual rupture of VEC junctions, thus facilitating egg transit out of the blood vessel. Overall, our data on the mechanical interplay between host VECs and the schistosome egg improve our understanding of how this parasite manipulates its immediate environment to maintain disease transmission.

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Renal interstitial hyaluronan: functional aspects during normal and pathological conditions

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00332.2011 ◽

2012 ◽

Vol 302 (11) ◽

pp. R1235-R1249 ◽

Cited By ~ 23

Author(s):

Sara Stridh ◽

Fredrik Palm ◽

Peter Hansell

Keyword(s):

Current Knowledge ◽

Stone Formation ◽

Ischemia Reperfusion ◽

The Body ◽

Receptor Expression ◽

Whole Body ◽

Hydration Status ◽

Hyaluronan Synthases ◽

Pathological Conditions

The glycosaminoglycan (GAG) hyaluronan (HA) is recognized as an important structural component of the extracellular matrix, but it also interacts with cells during embryonic development, wound healing, inflammation, and cancer; i.e., important features in normal and pathological conditions. The specific physicochemical properties of HA enable a unique hydration capacity, and in the last decade it was revealed that in the interstitium of the renal medulla, where the HA content is very high, it changes rapidly depending on the body hydration status while the HA content of the cortex remains unchanged at very low amounts. The kidney, which regulates fluid balance, uses HA dynamically for the regulation of whole body fluid homeostasis. Renomedullary HA elevation occurs in response to hydration and during dehydration the opposite occurs. The HA-induced alterations in the physicochemical characteristics of the interstitial space affects fluid flux; i.e., reabsorption. Antidiuretic hormone, nitric oxide, angiotensin II, and prostaglandins are classical hormones/compounds involved in renal fluid handling and are important regulators of HA turnover during variations in hydration status. One major producer of HA in the kidney is the renomedullary interstitial cell, which displays receptors and/or synthesis enzymes for the hormones mentioned above. During several kidney disease states, such as ischemia-reperfusion injury, tubulointerstitial inflammation, renal transplant rejection, diabetes, and kidney stone formation, HA is upregulated, which contributes to an abnormal phenotype. In these situations, cytokines and other growth factors are important stimulators. The immunosuppressant agent cyclosporine A is nephrotoxic and induces HA accumulation, which could be involved in graft rejection and edema formation. The use of hyaluronidase to reduce pathologically overexpressed levels of tissue HA is a potential therapeutic tool since diuretics are less efficient in removing water bound to HA in the interstitium. Although the majority of data describing the role of HA originate from animal and cell studies, the available data from humans demonstrate that an upregulation of HA also occurs in diabetic kidneys, in transplant-rejected kidneys, and during acute tubular necrosis. This review summarizes the current knowledge regarding interstitial HA in the role of regulating kidney function during normal and pathological conditions. It encompasses mechanistic insights into the background of the heterogeneous intrarenal distribution of HA; i.e., late nephrogenesis, its regulation during variations in hydration status, and its involvement during several pathological conditions. Changes in hyaluronan synthases, hyaluronidases, and binding receptor expression are discussed in parallel.

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Airway epithelium and bronchial reactivity

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-076 ◽

1987 ◽

Vol 65 (3) ◽

pp. 448-450 ◽

Cited By ~ 20

Author(s):

P. M. Vanhoutte

Keyword(s):

Epithelial Cells ◽

Airway Epithelium ◽

Vessel Wall ◽

Vascular System ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Blood Vessel Wall ◽

Respiratory Epithelial Cells ◽

Relaxing Factor ◽

Respiratory Epithelial

Damage to or dysfunction of respiratory epithelial cells may contribute to the etiology of bronchial hyperreactivity in asthma and airway infection. In the vascular system, endogenous neurohumoral mediators can cause either relaxation or contraction of the smooth muscle of the blood vessel wall because they cause the release of relaxing or contracting factor(s), respectively, from the vascular endothelial cells. This brief overview summarizes data from the author's laboratory, which suggests that release of relaxing factor(s) from epithelial cells contributes to the regulation of bronchomotor tone.

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Prox1 expression is negatively regulated by miR-181 in endothelial cells

Blood ◽

10.1182/blood-2009-12-256297 ◽

2010 ◽

Vol 116 (13) ◽

pp. 2395-2401 ◽

Cited By ~ 112

Author(s):

Jan Kazenwadel ◽

Michael Z. Michael ◽

Natasha L. Harvey

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Fate ◽

Vascular Endothelial Cells ◽

Vascular Development ◽

Lymphatic Endothelial Cell ◽

Mrna Levels ◽

Vascular Endothelial ◽

Lymphatic Endothelial Cells ◽

Prox1 Expression

Abstract The specification of arterial, venous, and lymphatic endothelial cell fate is critical during vascular development. Although the homeobox transcription factor, Prox1, is crucial for the specification and maintenance of lymphatic endothelial cell identity, little is known regarding the mechanisms that regulate Prox1 expression. Here we demonstrate that miR-181a binds the 3′ untranslated region of Prox1, resulting in translational inhibition and transcript degradation. Increased miR-181a activity in primary embryonic lymphatic endothelial cells resulted in substantially reduced levels of Prox1 mRNA and protein and reprogramming of lymphatic endothelial cells toward a blood vascular phenotype. Conversely, treatment of primary embryonic blood vascular endothelial cells with miR-181a antagomir resulted in increased Prox1 mRNA levels. miR-181a expression is significantly higher in embryonic blood vascular endothelial cells compared with lymphatic endothelial cells, suggesting that miR-181 activity could be an important mechanism by which Prox1 expression is silenced in the blood vasculature during development. Our work is the first example of a microRNA that targets Prox1 and has implications for the control of Prox1 expression during vascular development and neo-lymphangiogenesis.

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Extracellular vesicles: new players in regulating vascular barrier function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00579.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. H1181-H1196

Author(s):

Victor Chatterjee ◽

Xiaoyuan Yang ◽

Yonggang Ma ◽

Mack H. Wu ◽

Sarah Y. Yuan

Keyword(s):

Extracellular Vesicles ◽

Therapeutic Potential ◽

Current Knowledge ◽

Target Cells ◽

Vascular Endothelial ◽

Barrier Dysfunction ◽

Diagnosis And Prognosis ◽

Isolation And Characterization ◽

Pathological Conditions ◽

Inflammatory Response To Injury

Extracellular vesicles (EVs) have attracted rising interests in the cardiovascular field not only because they serve as serological markers for circulatory disorders but also because they participate in important physiological responses to stress and inflammation. In the circulation, these membranous vesicles are mainly derived from blood or vascular cells, and they carry cargos with distinct molecular signatures reflecting the origin and activation state of parent cells that produce them, thus providing a powerful tool for diagnosis and prognosis of pathological conditions. Functionally, circulating EVs mediate tissue-tissue communication by transporting bioactive cargos to local and distant sites, where they directly interact with target cells to alter their function. Recent evidence points to the critical contributions of EVs to the pathogenesis of vascular endothelial barrier dysfunction during inflammatory response to injury or infection. In this review, we provide a brief summary of the current knowledge on EV biology and advanced techniques in EV isolation and characterization. This is followed by a discussion focusing on the role and mechanisms of EVs in regulating blood-endothelium interactions and vascular permeability during inflammation. We conclude with a translational perspective on the diagnostic and therapeutic potential of EVs in vascular injury or infectious diseases, such as COVID-19.

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Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo

Development ◽

10.1242/dev.128.10.1717 ◽

2001 ◽

Vol 128 (10) ◽

pp. 1717-1730 ◽

Cited By ~ 3

Author(s):

M.A. Dyer ◽

S.M. Farrington ◽

D. Mohn ◽

J.R. Munday ◽

M.H. Baron

Keyword(s):

Endothelial Cells ◽

Cell Fate ◽

Mouse Embryo ◽

Hedgehog Signaling ◽

Vascular System ◽

Vascular Endothelial Cells ◽

Indian Hedgehog ◽

Vascular Endothelial ◽

Primitive Endoderm ◽

Genes Encoding

During gastrulation in the mouse, mesoderm is induced and patterned by secreted signaling molecules, giving rise first to primitive erythroblasts and vascular endothelial cells. We have demonstrated previously that development of these lineages requires a signal(s) secreted from the adjacent primitive endoderm. We now show that Indian hedgehog (Ihh) is a primitive endoderm-secreted signal that alone is sufficient to induce formation of hematopoietic and endothelial cells. Strikingly, as seen with primitive endoderm, Ihh can respecify prospective neural ectoderm (anterior epiblast) along hematopoietic and endothelial (posterior) lineages. Downstream targets of the hedgehog signaling pathway (the genes encoding patched, smoothened and Gli1) are upregulated in anterior epiblasts cultured in the presence of Ihh protein, as is Bmp4, which may mediate the effects of Ihh. Blocking Ihh function in primitive endoderm inhibits activation of hematopoiesis and vasculogenesis in the adjacent epiblast, suggesting that Ihh is an endogenous signal that plays a key role in the development of the earliest hemato-vascular system. To our knowledge, these are the earliest functions for a hedgehog protein in post-implantation development in the mouse embryo.

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The Role of Dll4/Notch Signaling in Normal and Pathological Ocular Angiogenesis: Dll4 Controls Blood Vessel Sprouting and Vessel Remodeling in Normal and Pathological Conditions

Journal of Ophthalmology ◽

10.1155/2018/3565292 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Ivan Lobov ◽

Natalia Mikhailova

Keyword(s):

Blood Vessel ◽

Transmembrane Protein ◽

Mammalian Species ◽

Vascular Development ◽

Critical Role ◽

Notch Pathway ◽

The Body ◽

Therapeutic Effects ◽

Pathological Conditions

Background. Retina is the highest oxygen-demanding and vascularized tissue in the body. Retinal development and function require proper vascularization and blood vessel function and integrity. Dll4 is most prominently expressed in the endothelium of angiogenic blood vessels and in quiescent arteries and capillaries in all tissues and organs of the mammalian species, and it is the key regulator of blood vessel sprouting.Results. Dll4 is a transmembrane protein that acts as a ligand for Notch receptors 1 and 4. Genetic deletion of Dll4 causes severe abnormalities in embryonic and postnatal vascular development. Deletion of even a single Dll4 allele results in almost complete embryonic lethality due to severe vascular abnormalities, the phenomenon called haploinsufficiency indicating the critical role of Dll4/Notch in vascular development. Dll4/Notch pathway interplays at multiple levels with other signaling pathways including VEGF, Wnt/Fzd, and genes controlling vascular toning. Multiple studies of the effects of Dll4 inhibition were performed in the developing retina to elucidate the key functions of Dll4 in normal and pathological angiogenesis. Several genetic approaches and therapeutic molecules were tested to evaluate the biological and therapeutic effects of acute and prolonged Dll4 inhibition in the eye and oncology.Conclusions. All current studies demonstrated that Dll4 controls blood vessel sprouting, growth, and remodeling in normal and pathological conditions as well as arterial-venous differentiation. Genetic and therapeutic Dll4 modulation studies show that Dll4 inhibition can promote blood vessel sprouting and might be useful to stimulate vessel growth in the ischemic retina and Dll4 is the key modulator of the postangiogenic vascular remodeling that ultimately defines vascular patterning.

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Vitamin D and Temporomandibular Disorders: What Do We Know So Far?

Nutrients ◽

10.3390/nu13041286 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1286

Author(s):

Andreea Kui ◽

Smaranda Buduru ◽

Anca Labunet ◽

Silvia Balhuc ◽

Marius Negucioiu

Keyword(s):

Vitamin D ◽

Temporomandibular Disorders ◽

Potential Role ◽

Current Knowledge ◽

Masticatory Muscles ◽

The Body ◽

Ultraviolet B ◽

Pathological Conditions ◽

Temporomandibular Joints

Background and aims. Vitamin D is synthesized in the skin with the aid of ultraviolet-B radiation, playing a variety of roles in the body. Temporomandibular disorders (TMDs) are a group of pathological conditions involving the temporomandibular joints as well as the masticatory muscles and othersurrounding tissues. In the present narrative review, we investigated the potential role of vitamin D in the etiology of temporomandibular disorders in order todetermine whether the current knowledge supports 25-hidroxyvitamin D (25-OHD) supplementation in temporomandibular disorders associated with insufficient or deficient levels of vitamin D. Methods. A literature research was performed in PubMed, Scopus, Science Direct, and Google Scholar databases, and a total of 10 articles were included for analysis. Results.Among the observational studies published to date, investigating the role for vitamin D in the etiology of TMDs, six of them suggest that there is a connection between the two aspects. In this context, patients suffering from TMD, with deficient levels of vitamin D (<30 ng/mL), are most likely to benefit from supplementation, whereas individuals with vitamin D level >50ng/mL probably have little benefit from supplementation.Conclusion.Vitamin D might be a safe, simple, and potentially beneficial way to prevent TMDs or to reduce pain; however, more randomized and placebo-controlled trials are required before any firm conclusions can be drawn.

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