scholarly journals Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2683
Author(s):  
Satu Paavonsalo ◽  
Sangeetha Hariharan ◽  
Madeleine H. Lackman ◽  
Sinem Karaman
Keyword(s):  
Metabolic Diseases ◽  
Vascular Dysfunction ◽  
Treatment Strategies ◽  
Organ Specificity ◽  
Paracrine Factors ◽  
Functional Changes ◽  
Capillary Rarefaction ◽  
Organ Specific ◽  
Endothelial Heterogeneity ◽  
Underlying Mechanisms

Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, causing morphological and functional changes in some tissues but not in others. Accordingly, treatment strategies targeting capillary rarefaction result in distinct outcomes depending on the organ. In recent years, organ-specific vasculature and endothelial heterogeneity have been in the spotlight in the field of vascular biology since specialized vascular systems have been shown to contribute to organ function by secreting varying autocrine and paracrine factors and by providing niches for stem cells. This review summarizes the recent literature covering studies on organ-specific capillary rarefaction observed in obesity and metabolic diseases and explores the underlying mechanisms, with multiple modes of action proposed. It also provides a glimpse of the reported therapeutic perspectives targeting capillary rarefaction. Further studies should address the reasons for such organ-specificity of capillary rarefaction, investigate strategies for its prevention and reversibility and examine potential signaling pathways that can be exploited to target it.

Targeting Tumour Metastasis: The Emerging Role of Nanotechnology

2020 ◽  
Vol 27 (8) ◽  
pp. 1367-1381 ◽  
Author(s):  
Sarah Visentin ◽  
Mirela Sedić ◽  
Sandra Kraljević Pavelić ◽  
Krešimir Pavelić
Keyword(s):  
Cancer Progression ◽  
Metastatic Cancer ◽  
Treatment Strategies ◽  
Metastatic Progression ◽  
Therapeutic Concept ◽  
Molecular Alterations ◽  
Tumour Metastasis ◽  
Metastatic Cells ◽  
Metastatic Process ◽  
Underlying Mechanisms

The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.

scholarly journals Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—A Condition Associated with Heightened Sympathetic Activation

2021 ◽  
Vol 22 (8) ◽  
pp. 4241
Author(s):  
Revathy Carnagarin ◽  
Kearney Tan ◽  
Leon Adams ◽  
Vance B. Matthews ◽  
Marcio G. Kiuchi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Metabolic Dysfunction ◽  
Sympathetic Activation ◽  
Beneficial Effects ◽  
Adverse Health Outcomes

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.

scholarly journals The Relationship between Frequently Used Glucose-Lowering Agents and Gut Microbiota in Type 2 Diabetes Mellitus

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
You Lv ◽  
Xue Zhao ◽  
Weiying Guo ◽  
Ying Gao ◽  
Shuo Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gut Microbiota ◽  
Metabolic Diseases ◽  
Short Chain Fatty Acids ◽  
Current Evidence ◽  
Diabetic Patients ◽  
Glucose Lowering ◽  
Patients With Diabetes ◽  
Gastrointestinal Side Effects ◽  
Underlying Mechanisms

Metabolic diseases, especially diabetes mellitus, have become global health issues. The etiology of diabetes mellitus can be attributed to genetic and/or environmental factors. Current evidence suggests the association of gut microbiota with metabolic diseases. However, the effects of glucose-lowering agents on gut microbiota are poorly understood. Several studies revealed that these agents affect the composition and diversity of gut microbiota and consequently improve glucose metabolism and energy balance. Possible underlying mechanisms include affecting gene expression, lowering levels of inflammatory cytokines, and regulating the production of short-chain fatty acids. In addition, gut microbiota may alleviate adverse effects caused by glucose-lowering agents, and this can be especially beneficial in diabetic patients who experience severe gastrointestinal side effects and have to discontinue these agents. In conclusion, gut microbiota may provide a novel viewpoint for the treatment of patients with diabetes mellitus.

Mechanisms involved in developmental programming of hypertension and renal diseases. Gender differences

2014 ◽  
Vol 18 (2) ◽  
Author(s):  
Analia Lorena Tomat ◽  
Francisco Javier Salazar
Keyword(s):  
Metabolic Diseases ◽  
Current Knowledge ◽  
Adult Life ◽  
Developmental Programming ◽  
Renal Diseases ◽  
Future Studies ◽  
Functional Changes ◽  
Regulatory Systems ◽  
Increased Risk ◽  
Renal Changes

AbstractA substantial body of epidemiological and experimental evidence suggests that a poor fetal and neonatal environment may “program” susceptibility in the offspring to later development of cardiovascular, renal and metabolic diseases.This review focuses on current knowledge from the available literature regarding the mechanisms linking an adverse developmental environment with an increased risk for cardiovascular, renal and metabolic diseases in adult life. Moreover, this review highlights important sex-dependent differences in the adaptation to developmental insults.Developmental programming of several diseases is secondary to changes in different mechanisms inducing important alterations in the normal development of several organs that lead to significant changes in birth weight. The different diseases occurring as a consequence of an adverse environment during development are secondary to morphological and functional cardiovascular and renal changes, to epigenetic changes and to an activation of several hormonal and regulatory systems, such as angiotensin II, sympathetic activity, nitric oxide, COX2-derived metabolites, oxidative stress and inflammation. The important sex-dependent differences in the developmental programming of diseases seem to be partly secondary to the effects of sex hormones. Recent studies have shown that the progression of these diseases is accelerated during aging in both sexes.The cardiovascular, renal and metabolic diseases during adult life that occur as a consequence of several insults during fetal and postnatal periods are secondary to multiple structural and functional changes. Future studies are needed in order to prevent the origin and reduce the incidence and consequences of developmental programmed diseases.

Abstract P604: Astrocyte-dependent Regulation of Vascular Tone: Role in Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Juan Manuel Ramiro-Diaz ◽  
Ki Jung Kim ◽  
Jessica A Filosa
Keyword(s):  
Vascular Tone ◽  
Structural Changes ◽  
Neurovascular Unit ◽  
Brain Slices ◽  
Vascular Cognitive Impairment ◽  
Vascular Density ◽  
Aqp4 Expression ◽  
Functional Changes ◽  
Functional Studies ◽  
Underlying Mechanisms

Clinical studies support that untreated hypertension (HT) accelerates the development of vascular cognitive impairment (VCI). Yet, the underlying mechanisms for VCI are not known. In a recent study we demonstrated the role of astrocytes in the regulation of parenchymal arteriole (PA) steady-state vascular tone. Here we hypothesized hypertension results in structural and functional changes to the neurovascular unit resulting in enhanced astrocytic TRPV4 channel-dependent Ca 2+ increases contributing to augmented pressure-induced PA constriction . Functional studies were conducted in brain slices from angiotensin II (AngII) treated mice (600 ng/Kg/min, 28 days). PA arterioles within brain slices were perfused and pressurized and myogenic-evoked diameter changes measured using video microscopy. In addition, using the GLAST-CreERT2 ; R26-lsl-GCaMP3 mice we measure myogenic-evoked Ca 2+ changes in perivascular astrocytes. We demonstrate that HT increases pressure-induced PA tone by 11.14% at 30 mmHg and 12.97% at 60 mmHg (10.88 to 22.02 and 15.46 to 28.43% of tone, P<0.05 and P<0.01, respectively). In ANG II-treated mice, PA myogenic-evoked responses significantly increased astrocytic Ca 2+ oscillations frequency (119.4%, 0.0366 to 0.0803 Hz, P<0.0001). A significant increase in astrocytic Ca 2+ oscillation frequency was also observed after 2 min of AngII (500 nM) bath application (44.8%, 0.0366 to 0.053 Hz, P<0.01) in brain slices from AngII treated mice. Furthermore, using the model of spontaneous hypertensive rat (SHR) we observed that HT differentially increases vascular density and the number of vascular pericytes in cortical layers with highest neuronal densities (L III-V). Finally, while aquaporin 4 (AQP4) expression pattern was not different in the gray matter of SHR compared with WKY rats, a significant increase in unpolarized AQP4 expression was observed in the white matter of SHR. Taken together, this evidence indicates that HT induces functional and structural changes to the neurovascular unit favoring the development of regional brain hypoperfusion likely contributing to the development of VCI.

scholarly journals Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies

2019 ◽  
Vol 116 (7) ◽  
pp. 2662-2671 ◽  
Author(s):  
Chrysovalantis Voutouri ◽  
Nathaniel D. Kirkpatrick ◽  
Euiheon Chung ◽  
Fotios Mpekris ◽  
James W. Baish ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Tumor Evolution ◽  
Combination Therapies ◽  
Tumor Vessel ◽  
Antiangiogenic Treatment ◽  
Antiangiogenic Drugs ◽  
Underlying Mechanisms ◽  
Computational Analyses

Cooption of the host vasculature is a strategy that some cancers use to sustain tumor progression without—or before—angiogenesis or in response to antiangiogenic therapy. Facilitated by certain growth factors, cooption can mediate tumor infiltration and confer resistance to antiangiogenic drugs. Unfortunately, this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood. Here, we analyzed the dynamics of vessel cooption during tumor progression and in response to antiangiogenic treatment in gliomas and brain metastases. We followed tumor evolution during escape from antiangiogenic treatment as cancer cells coopted, and apparently mechanically compressed, host vessels. To gain deeper understanding, we developed a mathematical model, which incorporated compression of coopted vessels, resulting in hypoxia and formation of new vessels by angiogenesis. Even if antiangiogenic therapy can block such secondary angiogenesis, the tumor can sustain itself by coopting existing vessels. Hence, tumor progression can only be stopped by combination therapies that judiciously block both angiogenesis and cooption. Furthermore, the model suggests that sequential blockade is likely to be more beneficial than simultaneous blockade.

Potentiation to vasodilators by nitric oxide synthase blockade in superior mesenteric but not hepatic artery

1997 ◽  
Vol 272 (3) ◽  
pp. G507-G514 ◽  
Author(s):  
M. P. Macedo ◽  
W. W. Lautt
Keyword(s):  
Nitric Oxide ◽  
Hepatic Artery ◽  
Organ Specificity ◽  
No Production ◽  
Compensatory Mechanism ◽  
Basal Tone ◽  
Before And After ◽  
Organ Specific ◽  
Pentobarbital Sodium Anesthesia ◽  
Oxide Synthase

Our objective was to determine the vasodilator effect of adenosine and isoproterenol on the hepatic artery (HA) and superior mesenteric artery (SMA) before and after blockade of nitric oxide (NO) production to evaluate the possibility of organ specificity. Vascular circuits supplied blood flow to the liver or intestine in cats under pentobarbital sodium anesthesia. The NO synthase (NOS) antagonist N(G)-nitro-L-arginine methyl ester (L-NAME; 2.5 mg/kg iv) increased arterial pressure from 106.4 +/- 7.6 to 141.4 +/- 8.1 mmHg and raised basal vascular tone in the SMA but not in the HA. The NOS substrate L-arginine (75 mg/kg) reversed these effects. The decrease in perfusion pressure in response to adenosine was 51.7 +/- 2.9, 135.2 +/- 6.1, and 16.7 +/- 2.4 mmHg, respectively, for control and after L-NAME and L-arginine. Isoproterenol was also potentiated in the SMA. Adenosine and isoproterenol were not potentiated in the HA by L-NAME. Potentiation did not occur when HA or SMA basal tone was elevated by norepinephrine. In conclusion, L-NAME increased basal tone for the SMA and potentiated the dilation induced by adenosine and isoproterenol in the SMA but not in the HA. This study provides evidence that there is a highly organ-specific compensatory mechanism in which the absence of NO promotes potentiation of other vasodilators.

scholarly journals Analyzing Impetus of Regenerative Cellular Therapeutics in Myocardial Infarction

2020 ◽  
Vol 9 (5) ◽  
pp. 1277 ◽  
Author(s):  
Ming-Long Chang ◽  
Yu-Jui Chiu ◽  
Jian-Sing Li ◽  
Khoot-Peng Cheah ◽  
Hsiu-Hu Lin
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Cardiac Fibroblasts ◽  
Cell Lineage ◽  
Specific Cell ◽  
Paracrine Factors ◽  
Differentiation Potential ◽  
Cell Based Therapy ◽  
Organ Specific ◽  
Made In

Both vasculature and myocardium in the heart are excessively damaged following myocardial infarction (MI), hence therapeutic strategies for treating MI hearts should concurrently aim for true cardiac repair by introducing new cardiomyocytes to replace lost or injured ones. Of them, mesenchymal stem cells (MSCs) have long been considered a promising candidate for cell-based therapy due to their unspecialized, proliferative differentiation potential to specific cell lineage and, most importantly, their capacity of secreting beneficial paracrine factors which further promote neovascularization, angiogenesis, and cell survival. As a consequence, the differentiated MSCs could multiply and replace the damaged tissues to and turn into tissue- or organ-specific cells with specialized functions. These cells are also known to release potent anti-fibrotic factors including matrix metalloproteinases, which inhibit the proliferation of cardiac fibroblasts, thereby attenuating fibrosis. To achieve the highest possible therapeutic efficacy of stem cells, the other interventions, including hydrogels, electrical stimulations, or platelet-derived biomaterials, have been supplemented, which have resulted in a narrow to broad range of outcomes. Therefore, this article comprehensively analyzed the progress made in stem cells and combinatorial therapies to rescue infarcted myocardium.

scholarly journals Current and Future Treatments in Alzheimer Disease: An Update

2020 ◽  
Vol 12 ◽  
pp. 117957352090739 ◽  
Author(s):  
Konstantina G Yiannopoulou ◽  
Sokratis G Papageorgiou
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Neurofibrillary Tangle ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Amyloid Β ◽  
Cell Therapies ◽  
Novel Biomarkers ◽  
Disease Modifying ◽  
Underlying Mechanisms

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

scholarly journals Open microfluidic coculture reveals paracrine signaling from human kidney epithelial cells promotes kidney specificity of endothelial cells

2020 ◽  
Vol 319 (1) ◽  
pp. F41-F51
Author(s):  
Tianzi Zhang ◽  
Daniel Lih ◽  
Ryan J. Nagao ◽  
Jun Xue ◽  
Erwin Berthier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Matrix Metalloproteinase ◽  
Culture Media ◽  
Human Kidney ◽  
Organ Specificity ◽  
Paracrine Signaling ◽  
Human Organ ◽  
Extrinsic Cues ◽  
Organ Specific

Endothelial cells (ECs) from different human organs possess organ-specific characteristics that support specific tissue regeneration and organ development. EC specificity is identified by both intrinsic and extrinsic cues, among which the parenchyma and organ-specific microenvironment are critical contributors. These extrinsic cues are, however, largely lost during ex vivo cultures. Outstanding challenges remain to understand and reestablish EC organ specificity for in vitro studies to recapitulate human organ-specific physiology. Here, we designed an open microfluidic platform to study the role of human kidney tubular epithelial cells in supporting EC specificity. The platform consists of two independent cell culture regions segregated with a half wall; culture media are added to connect the two culture regions at a desired time point, and signaling molecules can travel across the half wall (paracrine signaling). Specifically, we report that in the microscale coculture device, primary human kidney proximal tubule epithelial cells (HPTECs) rescued primary human kidney peritubular microvascular EC (HKMEC) monolayer integrity and fenestra formation and that HPTECs upregulated key HKMEC kidney-specific genes (hepatocyte nuclear factor 1 homeobox B, adherens junctions-associated protein 1, and potassium voltage-gated channel subfamily J member 16) and endothelial activation genes (vascular cell adhesion molecule-1, matrix metalloproteinase-7, and matrix metalloproteinase-10) in coculture. Coculturing with HPTECs also promoted kidney-specific genotype expression in human umbilical vein ECs and human pluripotent stem cell-derived ECs. Compared with culture in HPTEC conditioned media, coculture of ECs with HPTECs showed increased upregulation of kidney-specific genes, suggesting potential bidirectional paracrine signaling. Importantly, our device is compatible with standard pipettes, incubators, and imaging readouts and could also be easily adapted to study cell signaling between other rare or sensitive cells.

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