Glycyrrhetinic acid antagonizes pressure-induced venous remodeling in mice
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ABSTRACT:
PROVIDER: PRJNA433489 | ENA |
REPOSITORIES: ENA
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Project description:Development of spider veins is caused by the remodeling of veins located in the upper dermis and promoted by risk factors such as obesity or pregnancy that chronically increase venous pressure. We have repeatedly shown that the pressure-induced increase in biomechanical wall stress is sufficient to evoke the formation of enlarged corkscrew-like superficial veins in mice. Subsequent experimental approaches revealed that interference with endothelial- and/or smooth muscle cell activation counteracts this remodeling process. Here, we investigate whether the herbal agent glycyrrhetinic acid (GA) is a suitable candidate for that purpose given its anti-proliferative as well as anti-oxidative properties. While basic abilities of cultured venous smooth muscle cells (SMCs) such as migration and proliferation were not influenced by GA, it inhibited proliferation but not angiogenic sprouting of human venous endothelial cells (ECs). Further analyses of biomechanically stimulated ECs revealed that GA inhibits the DNA binding capacity of the mechanosensitive transcription factor activator protein-1 (AP-1) which, however, had only a minor impact on the endothelial transcriptome. Nevertheless, by decreasing gelatinase activity in ECs or mouse veins exposed to biomechanical stress, GA diminished a crucial cellular response in the context of venous remodeling. In line with the observed inhibitory effects, local transdermal application of GA attenuated pressure-mediated enlargement of veins in the mouse auricle. In summary, our data identifies GA as an inhibitor of EC proliferation, gelatinase activity and venous remodeling. It may thus have the capacity to attenuate spider vein formation and remodeling in humans.
2018-03-23 | GSE110335 | GEO
Project description:Development of spider veins is caused by the remodeling of veins located in the upper dermis and promoted by risk factors such as obesity or pregnancy that chronically increase venous pressure. We have repeatedly shown that the pressure-induced increase in biomechanical wall stress is sufficient to evoke the formation of enlarged corkscrew-like superficial veins in mice. Subsequent experimental approaches revealed that interference with endothelial- and/or smooth muscle cell (SMC) activation counteracts this remodeling process. Here, we investigate whether the herbal agent glycyrrhetinic acid (GA) is a suitable candidate for that purpose given its anti-proliferative as well as anti-oxidative properties. While basic abilities of cultured venous SMCs such as migration and proliferation were not influenced by GA, it inhibited proliferation but not angiogenic sprouting of human venous endothelial cells (ECs). Further analyses of biomechanically stimulated ECs revealed that GA inhibits the DNA binding capacity of the mechanosensitive transcription factor activator protein-1 (AP-1) which, however, had only a minor impact on the endothelial transcriptome. Nevertheless, by decreasing gelatinase activity in ECs or mouse veins exposed to biomechanical stress, GA diminished a crucial cellular response in the context of venous remodeling. In line with the observed inhibitory effects, local transdermal application of GA attenuated pressure-mediated enlargement of veins in the mouse auricle. In summary, our data identifies GA as an inhibitor of EC proliferation, gelatinase activity and venous remodeling. It may thus have the capacity to attenuate spider vein formation and remodeling in humans.
| S-EPMC5893715 | biostudies-literature
Project description:Two matched groups of Heart Failure with reduced ejection fraction patients with no peripheral venous congestion were studied: with recent prior heart failure hospitalization vs. without recent heart failure hospitalization. Peripheral venous congestion was modeled by inflating a cuff around the dominant arm, targeting an ~30mmHg increase in venous pressure (venous stress test). Blood and endothelial cells were sampled before and after 90 minutes of venous stress test.
2023-08-28 | GSE237856 | GEO
Project description:Chronic cerebral hypoperfusion, induced by bilateral common carotid artery stenosis (BCAS), models the underlying cause of vascular dementia. We used single-cell transcriptomics to identify endothelial subtype-specific responses to BCAS in the mouse prefrontal cortex. The most dynamic molecular changes were observed in venous endothelial cells, with upregulated pathways linked to vascular remodeling and angiogenesis. Cerebral hypoperfusion upregulated expression of the endothelial PAS domain protein 1 (Epas1 ) gene in venous endothelial cells, while exposure of human venous endothelial cells to 1% oxygen in vitro caused sustained nuclear translocation of EPAS1. Pharmacological inhibition of EPAS1 reduced abnormal venous sprouting and concomitantly dampened microglia activation. Among human subjects with mild cerebrovascular disease, there was a negative correlation observed between their circulating damaged endothelial cells (CECs) and cerebral blood flow levels. In addition, elevated levels of venous-origin CECs were detected in subjects with white matter lesions and were notably linked to poorer overall cognitive function. We conclude that venous endothelial cells are potential therapeutic targets for vessel normalization to mitigate vascular cognitive impairment caused by chronic cerebral hypoperfusion.
2025-05-27 | GSE263191 | GEO
Project description:BACKGROUND: As evidenced by epidemiological and etiological studies, the development of varicose veins is driven by risk-factors which support the development of venous hypertension and thus chronically augment circumferential stress of the venous wall (e.g. dysfunctional venous valves, pregnancy or obesity). We have previously verified the relevance of this biomechanical stimulus for the activation of venous endothelial as well as smooth muscle cells and the subsequent detrimental structural remodeling of the vein wall in experimental mouse models. METHODS: Here, transcriptome analyses revealed an increase in the expression of cyclooxygenase 2 (COX-2) in human venous endothelial cells upon exposure to biomechanical stress. Subsequently, we investigated the impact of diclofenac – a cyclooxygenase inhibitor – on responses of isolated mouse veins to augmented wall stress in vitro and on varicose-like venous remodeling in vivo. RESULTS: Diclofenac treatment decreased COX-2 protein abundance in mouse veins but had no significant impact on the expression of corresponding transcripts. Short-term exposure to elevated pressure levels stimulated the activity of matrix-metalloproteinase-2 (MMP-2) and mitogen activated protein kinases ERK1/2. Diclofenac decreased the level of activated MMP-2 and ERK1/2 in pressure-exposed mouse veins. Varikose-like remodeling of veins in the mouse auricle was significantly inhibited by transdermal application of diclofenac-containing phospholipid-micelles. This effect was associated with decreased COX-2 and MMP-2 abundance as well as cell proliferation. CONCLUSION: The cyclooxygenase inhibitor diclofenac interferes with short term activation of MAP-kinases and matrix-metalloproteinases in cells of the wall stress-exposed venous wall while attenuating venous remodeling in vivo. Thus, nonsteroidal anti-inflammatory drugs may be suitable to interfere with processes promoting the progression of varicose vein development and biomechanical activation of venous cells.
2021-01-12 | GSE121557 | GEO
Project description:Chronic Cerebral Hypoperfusion Induces Pathological Venous Remodeling via EPAS1 Regulation
| PRJNA1096111 | ENA
Project description:Background: Venous hypertension is often present in advanced and in acute decompensated heart failure (HF). However, it is unclear whether high intravenous pressure can cause alterations in homeostasis by promoting inflammation and endothelial cell (EC) activation. We used an experimental model of acute, local venous hypertension to study the changes in circulating inflammatory mediators and EC phenotype that occur in response to biomechanical stress. Methods and Results: Twenty-four healthy subjects (14 men, age 35±2 years) were studied. Venous arm pressure was increased to ~30 mmHg above baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 minutes of venous hypertension, using angiocatheters and endovascular wires. Magnetic beads coated with EC specific antibodies were used for EC separation; amplified mRNA was analyzed by Affymetrix HG-U133 2.0 Microarray. Plasma endothelin-1 (ET-1), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. 5,332 probe sets were differentially expressed in venous ECs before vs. after testing. Among the 143 probe sets that exhibited a significant absolute fold change >2, we identified several inflammatory mediators including ET-1, VCAM-1, and CXCL2. Conclusions: Acute experimental venous hypertension is sufficient to cause local increase in circulating inflammatory mediators and to activate venous ECs in healthy human subjects. Additional work is needed to determine the effect of venous hypertension in patients with established HF. 24 samples were analyzed from 12 patients. Each patient contributed 2 samples (1 prior to intervention and 1 after intervention). The pre-intervention sample serves as the control.
2013-12-04 | E-GEOD-38783 | biostudies-arrayexpress
Project description:Background: Venous hypertension is often present in advanced and in acute decompensated heart failure (HF). However, it is unclear whether high intravenous pressure can cause alterations in homeostasis by promoting inflammation and endothelial cell (EC) activation. We used an experimental model of acute, local venous hypertension to study the changes in circulating inflammatory mediators and EC phenotype that occur in response to biomechanical stress. Methods and Results: Twenty-four healthy subjects (14 men, age 35±2 years) were studied. Venous arm pressure was increased to ~30 mmHg above baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 minutes of venous hypertension, using angiocatheters and endovascular wires. Magnetic beads coated with EC specific antibodies were used for EC separation; amplified mRNA was analyzed by Affymetrix HG-U133 2.0 Microarray. Plasma endothelin-1 (ET-1), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. 5,332 probe sets were differentially expressed in venous ECs before vs. after testing. Among the 143 probe sets that exhibited a significant absolute fold change >2, we identified several inflammatory mediators including ET-1, VCAM-1, and CXCL2. Conclusions: Acute experimental venous hypertension is sufficient to cause local increase in circulating inflammatory mediators and to activate venous ECs in healthy human subjects. Additional work is needed to determine the effect of venous hypertension in patients with established HF.
2013-12-04 | GSE38783 | GEO
Project description:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
2025-02-28 | GSE260465 | GEO
Project description:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
2025-02-28 | GSE260464 | GEO