Cardiac-Vascular Remodeling and Functional Interaction

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High intraluminal pressures also cause superoxide production via activation of NADPH oxidase in intact isolated vessels, an effect that is independent of the local renin—angiotensin system Activation of mechanically sensitive redox signaling pathways may thus contribute to some of the maladaptive responses to altered hemodynamics in hypertension. Similar results were obtained using an organ culture model of rabbit aorta.

Other studies suggested additional mechanisms and demonstrated that in cell culture model of arterial hypertension CS induced ROS production via NADPH oxidase and led to vascular remodeling via matrix metalloproteinase activation Therefore, increased oxidative stress in response to stretch contributes to activation of pro-inflammatory transcription factors, activation of growth-promoting MAP kinases, upregulation of pro-fibrogenic mediators and altered vascular tone, important processes contributing to the vascular phenotype associated with hypertension Fig.

Role of ROS in cyclic stretch-induced vascular remodeling and endothelial activation.

Endocardial function in pacing-induced heart failure in the dog. - Semantic Scholar

Mechanical ventilation with oxygen-enriched gas mixtures is a strategy widely employed to improve arterial oxygenation in patients with acute hypoxemic respiratory failure. However, combination of excessive ventilation and hyperoxia can damage normal lung tissue and initiate or exacerbate lung injury. Ventilation at high tidal volumes combined with hyperoxia significantly increased edema formation and neutrophil migration into the lungs , indicating critical changes in pulmonary vascular permeability.

In endothelium, mechanical stretch has been shown to increase ROS production leading to the upregulation of cell adhesion molecules and chemokines 40 , Kuebler et al. We suggested that these mechanisms also may contribute to the development of VILI 1. Ali et al.

Further studies by this group reported that mitochondrial oxidants generated in response to endothelial strain trigger FAK phosphorylation through a signaling pathway that involves PKC 5. These results suggest an interesting possibility for mitochondria being functional mechanotransducers in endothelial cells, regulating pulmonary vascular barrier function via a ROS-mediated effect on redox-sensitive signaling protein kinases.

Taken together, these studies suggest an important role of ROS signaling in mechanochemical regulation of endothelial cell remodeling and pulmonary vascular permeability. Like other tissue, blood vessels experience a complex pattern of mechanical and chemical stimulations in physiological and pathological conditions. Lung vascular permeability to water and proteins is also controlled by vascular endothelial growth factor VEGF.

lncRNA/MicroRNA interactions in the vasculature

However, the role of VEGF in lung pathology is controversial. VEGF is primarily produced by type II alveolar epithelial cells and is a survival factor for the lung microvascular endothelial cells However, under conditions of stress or injury such as in ALI or VILI, because of anatomic proximity between alveolar epithelial and microvascular endothelial cells, VEGF may literally spill onto pulmonary EC, increasing permeability and leading to interstitial and pulmonary edema 78 , High tidal volume ventilation and cyclic stretch of vascular endothelial and smooth muscle cells in vitro also stimulates VEGF and VEGF receptor expression 63 , , It is proposed, but not tested experimentally, that mechanical forces associated with mechanical ventilation may possess synergistic effects on the VEGF-induced ROS production.

Furthermore, the crosstalk between physiologically and pathologically relevant amplitudes of cyclic stretch and VEGF effects on pulmonary vascular permeability is not yet clear. Cyclic stretch stimulation of pulmonary arterial smooth muscle cells contributed to vascular remodeling via increase in VEGF expression that was mediated by stretch-induced activation of NADPH oxidase and elevation of ROS production Our results show that similar to smooth muscle cells, cyclic stretch stimulation of pulmonary endothelial cells promoted VEGF-induced EC barrier dysfunction in part via synergistic effects on ROS production Figs.

Inhibition of ROS production by N-acetyl cysteine significantly decreased endothelial cytoskeletal remodeling and barrier dysfunction induced by VEGF and pathologic amplitudes of cyclic stretch Fig. These functional interactions between VEGF- and cyclic stretch-mediated pathways and delineation of the role of ROS production in endothelial signaling, cytoskeletal regulation, and increased pulmonary vascular permeability are in the focus of our current studies.

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A Immunoflourescence staining of F-actin was performed using Texas Red conjugated phalloidin. Arrows indicate cyclic stretch- and VEGF-induced paracellular gap formation. This review summarized mechanisms of ROS production induced by cyclic stretch or agonists angiotensin-II. However, in physiologic milieu, signaling by chemical and mechanical stimuli is highly interconnected.

Thus, interactions between cyclic stretch and agonist stimulation may represent a fundamental mechanism of mechanochemical control of vascular remodeling and barrier function. For example, our previous studies have shown synergistic effect of high magnitude cyclic stretch on thrombin-induced pulmonary endothelial barrier dysfunction, which resulted from increased actomyosin contraction mediated by the Rho pathway 23 , Because thrombin-mediated signal transduction also involves ROS-dependent mechanism 17 , potentiation of thrombin-induced endothelial permeability by high magnitude cyclic stretch may share a common mechanism with stretch-VEGF signaling described above.

The other part of stretch-induced modulation of ROS signaling is feedback regulation of antioxidant systems. Some vascular genes encoding antioxidant enzymes appear to be upregulated by exercise training. These enzymes convert superoxide to the less active ROS compound, hydrogen peroxide. In turn, potentially pro-oxidant and atherogenic vascular proteins such as subunits of endothelial and vascular smooth muscle NADPH oxidase and angiotensin receptor type I were downregulated by exercise training 3 , The mechanisms by which cyclic stretch regulates the antioxidant enzyme expression remain poorly understood.

Our recent studies revealed involvement of the transcription factor Nrf2 in this process The transcription factor Nrf2, via the antioxidant response element ARE , alleviates pulmonary toxicant- and oxidant-induced oxidative stress by upregulating the expression of several antioxidant enzymes These findings again reflect tight relations between cyclic stretch and ROS in mechanochemical regulation of vascular function.

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Shear stress and tensile forces are now well-recognized factors that regulate endothelial signaling, cytoskeletal remodeling, gene expression, and physiological responses. The rapidly growing body of evidence indicates that endothelial cells discriminate between steady and cyclic, low and high amplitude mechanical strain. Moreover, the pattern of mechanical stimulation determines whether endothelial cells will develop pro- or anti-inflammatory cell responses and also may differentially regulate endothelial barrier regulation and vascular remodeling.

Experimental and analytical tools are being developed to assess the stress distribution throughout cell structures that might be involved in mechanotransduction. Studies by several groups suggest that in acute settings agonist-induced ROS production may be further enhanced by cyclic stretch. These synergistic effects may exacerbate pathologic reactions in the vasculature, for example, vascular leak during mechanical lung ventilation with ongoing oxidative stress caused by neutrophil activation or inflammatory cytokine production.

Another potential situation is the pulmonary hypertension with elevated angiotensin II levels, where increased luminal pressure may further potentiate ROS production and vascular remodeling triggered by angiotensin II. Redox balance in the pulmonary circulation is even more delicate in clinical settings of mechanical ventilation with oxygen-rich gas formulations. Finally, synergistic effects of VEGF and high magnitude stretch may further promote endothelial dysfunction and vascular remodeling associated with hemodynamic perturbations and acute vascular injury conditions.

However, stretch- and agonist-induced oxidative stress in the vasculature appears to be counterbalanced by upregulation of antioxidant enzymes via negative feedback signaling loops, and involvement of Nrf2 in stretch-induced antioxidant enzyme transcriptional regulation appears to be a plausible mechanism. A challenging task of future studies will be to address a role of specific patterns of mechanical forces experienced by vasculature in physiological and pathological conditions acute injury, inflammation, hypertension, ventilator-induced lung injury , delineate synergistic mechanisms of mechanical and chemical stimulation in the redox regulation of vascular function, and will identify key cellular targets for drug design and gene therapy.

The author thanks Dr. Anna Birukova for invaluable comments in preparing the manuscript and for superior assistance in figure preparation. Europe PMC requires Javascript to function effectively. Recent Activity. The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Antioxid Redox Signal. PMID: Konstantin G. Corresponding author. Address reprint requests to: Konstantin G.

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    This article has been cited by other articles in PMC. Abstract Blood vessels respond to changes in mechanical load from circulating blood in the form of shear stress and mechanical strain as the result of heart propulsions by changes in intracellular signaling leading to changes in vascular tone, production of vasoactive molecules, and changes in vascular permeability, gene regulation, and vascular remodeling.

    Introduction B lood vessels are permanently exposed to hemodynamic forces in the form of shear stress and circumferential mechanical strain, which act on the vascular wall and play an important role in the regulation of vascular structure, myogenic tone, and functional responses to vasoactive agonists. Biology of ROS Cellular respiration in an oxygen-rich environment generates abundant derivatives of partially reduced oxygen, collectively termed reactive oxygen species ROS.

    Open in a separate window. ROS Metabolism and Vascular Wall ROS are produced by all vascular cell types, including endothelial, smooth muscle, and adventitial cells, and can be generated from both metabolic and enzymatic sources Fig.

    Xanthine oxidase Another source of vascular ROS is the xanthine oxidoreductase enzyme system. Mitochondrial respiratory chain The mitochondrial respiratory chain is the main energy source for the cell. ROS and Vascular Disease Although the sources described above are primarily responsible for ambient ROS production and basal cellular homeostatic function, when vascular disease states ensue, redox balance in the vessel wall is compromised because of increased ROS production by these sources. ROS and hypertension An increasing body of evidence supports the idea that ROS are involved in the pathogenesis of hypertension.

    ROS and pulmonary vascular dysfunction Adult respiratory distress syndrome ARDS or acute lung injury ALI is a common response of the lung to diverse clinical insults, including sepsis, pneumonia, trauma, aspiration, and ventilator-induced lung injury VILI Biology of Cyclic Stretch Blood vessels are permanently exposed to mechanical stresses, and alterations in these forces are thought to be important in vascular remodeling in both physiological conditions, such as exercise training, and in pathological conditions, such as hypertension, atherosclerosis, and diabetes 4 , 81 , Cyclic stretch and vascular diseases The increase in vascular wall stress associated with hypertension has been implicated in the pathogenesis of cardiovascular diseases.

    Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart

    Cyclic stretch in pulmonary vasculature In pulmonary circulation, pathological overdistension of the lung may induce inflammatory processes triggered by mechanical activation of macrophages, epithelial, and endothelial cells, which may cause alveolar and endothelial barrier dysfunction, vascular leak, and culminate in ventilator-induced lung injury VILI syndrome or pulmonary edema 49 , Stretch-Activated Cellular Signaling Cell membranes, cell attachment sites, and cytoskeletal network directly experience hemodynamic forces, and most likely serve as primary mechanosensors Major signaling pathways and cellular responses induced by cyclic stretch.

    Cyclic Stretch-Regulated Gene Expression Studies on the effects of mechanical stretch on vascular cells indicate that mechanical stretch has significant effects on the expression of genes related to vascular remodeling and cell functions such as cell proliferation, apoptosis, migration, and control of cell phenotype. Table 1. ROS in Stretch-Induced Vascular Remodeling Increased pressure in the vascular system is associated with cyclic or sustained stretch of vascular endothelial and smooth muscle cells. Cyclic Stretch and ROS-Dependent Endothelial Activation Mechanical ventilation with oxygen-enriched gas mixtures is a strategy widely employed to improve arterial oxygenation in patients with acute hypoxemic respiratory failure.

    Modulation of Stretch-Induced ROS Production and Vascular Functions Like other tissue, blood vessels experience a complex pattern of mechanical and chemical stimulations in physiological and pathological conditions. Conclusions Shear stress and tensile forces are now well-recognized factors that regulate endothelial signaling, cytoskeletal remodeling, gene expression, and physiological responses. Acknowledgments The author thanks Dr. References 1. Abdulnour RE. Peng X.

    Vascular remodelling

    Finigan JH. Han EJ. Hasan EJ. Birukov KG.

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