Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

2007 ◽  
Vol 43 ◽  
pp. 105-120 ◽  
Author(s):  
Michael L. Paffett ◽  
Benjimen R. Walker
Keyword(s):  
Vascular Tone ◽  
Cellular Proliferation ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factor ◽  
Systemic Circulation ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Vasoconstriction ◽  
Adaptive Mechanisms ◽  
Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

scholarly journals Dual role of the L-arginine–ADMA–NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction

2020 ◽  
Vol 10 (1_suppl) ◽  
pp. 23-30 ◽  
Author(s):  
Rainer Böger ◽  
Juliane Hannemann
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Endothelium ◽  
Asymmetric Dimethylarginine ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systemic Circulation ◽  
Pulmonary Vasoconstriction ◽  
Hypoxic Vasodilation ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

In healthy vascular endothelium, nitric oxide acts as a vasodilator paracrine mediator on adjacent smooth muscle cells. By activating soluble guanylyl cyclase, nitric oxide stimulates cyclic guanosine monophosphate (cGMP) which causes relaxation of vascular smooth muscle (vasodilation) and inhibition of platelet aggregation. This mechanism is active in both, the systemic and pulmonary circulation. In the systemic circulation, hypoxia results in local vasodilation, which has been shown to be brought about by stabilization of hypoxia-inducible factor-1α (HIF1α) and concomitant upregulation of endothelial nitric oxide synthase. By contrast, the physiological response to hypoxia in the pulmonary circulation is vasoconstriction. Hypoxia in the lung primarily results from hypoventilation of circumscript areas of the lung, e.g. by bronchial tree obstruction or inflammatory infiltration. Therefore, hypoxic pulmonary vasoconstriction is a mechanism preventing distribution of blood to hypoventilated areas of the lungs, thereby maintaining maximal oxygenation of blood. The exact molecular mechanism of hypoxic pulmonary vasoconstriction is less well understood than hypoxic vasodilation in the systemic circulation. While alveolar epithelial cells may be key in sensing low oxygen concentration, and pulmonary vascular smooth muscle cells obviously are the effectors of vasoconstriction, the pulmonary vascular endothelium plays a crucial role as an intermediate between these cell types. Indeed, dysfunctional endothelial nitric oxide release was observed in humans exposed to acute hypoxia, and animal studies suggest that hypoxic pulmonary vasoconstriction is enhanced by nitric oxide synthase inhibition. This may be caused, in part, by elevation of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthesis. High asymmetric dimethylarginine levels are associated with endothelial dysfunction, vascular disease, and hypertension.

scholarly journals Ceramide and Regulation of Vascular Tone

2019 ◽  
Vol 20 (2) ◽  
pp. 411 ◽  
Author(s):  
Angel Cogolludo ◽  
Eduardo Villamor ◽  
Francisco Perez-Vizcaino ◽  
Laura Moreno
Keyword(s):  
Lung Diseases ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Ductus Arteriosus ◽  
Complex Interaction ◽  
Oxygen Species ◽  
Pulmonary Vasoconstriction ◽  
Physiological Relevance ◽  
Regulation Of Vascular Tone

In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the regulation of vascular tone. Ceramide may induce vasodilator or vasoconstrictor effects by interacting with several signaling pathways in endothelial and smooth muscle cells. There is a clear, albeit complex, interaction between ceramide and redox signaling. In fact, reactive oxygen species (ROS) activate different ceramide generating pathways and, conversely, ceramide is known to increase ROS production. In recent years, ceramide has emerged as a novel key player in oxygen sensing in vascular cells and mediating vascular responses of crucial physiological relevance such as hypoxic pulmonary vasoconstriction (HPV) or normoxic ductus arteriosus constriction. Likewise, a growing body of evidence over the last years suggests that exaggerated production of vascular ceramide may have detrimental effects in a number of pathological processes including cardiovascular and lung diseases.

Effects of endogenous nitric oxide on pulmonary vascular tone in intact dogs

1994 ◽  
Vol 266 (6) ◽  
pp. H2343-H2347 ◽  
Author(s):  
M. Leeman ◽  
V. Z. de Beyl ◽  
M. Delcroix ◽  
R. Naeije
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Balloon Catheter ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Endogenous Nitric Oxide ◽  
Anesthetized Dogs

The interaction between inspiratory fraction of O2 (FIO2) and endogenous nitric oxide (NO) regulation of pulmonary vascular tone was examined in intact anesthetized dogs. Stimulus (FIO2 of 1, 0.4, 0.21, 0.12, and 0.1)-response (changes in pulmonary artery pressure minus pulmonary artery occlusion pressure) curves were constructed with cardiac output kept constant (by opening a femoral arteriovenous bypass or inflating an inferior vena cava balloon catheter), before and after administration of compounds acting at different levels of the L-arginine-NO pathway, NG-nitro-L-arginine (L-NNA, 10 mg/kg iv, n = 16), a NO synthase inhibitor, and methylene blue (8 mg/kg iv, n = 16), a guanylate cyclase inhibitor. L-NNA and methylene blue did not influence pulmonary vascular tone in hyperoxic and in normoxic conditions, but they increased it during hypoxia, thus enhancing the vasopressor response to hypoxia (from 4.5 +/- 0.9 to 10.4 +/- 1.2 mmHg and from 4.2 +/- 0.8 to 9 +/- 1.5 mmHg, respectively, both P < 0.01). Hypoxic pulmonary vasoconstriction was augmented in dogs with a baseline hypoxic response (“responders”) and restored in dogs without hypoxic response (“nonresponders”). These results suggest that endogenous NO does not influence hyperoxic and normoxic pulmonary vascular tone, but that it inhibits hypoxic pulmonary vasoconstriction in intact anesthetized dogs.

scholarly journals Lactate Stimulates Vasculogenic Stem Cells via the Thioredoxin System and Engages an Autocrine Activation Loop Involving Hypoxia-Inducible Factor 1

2008 ◽  
Vol 28 (20) ◽  
pp. 6248-6261 ◽  
Author(s):  
Tatyana N. Milovanova ◽  
Veena M. Bhopale ◽  
Elena M. Sorokina ◽  
Jonni S. Moore ◽  
Thomas K. Hunt ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Lactate Concentration ◽  
Systemic Circulation ◽  
Hypoxia Inducible Factor 1 ◽  
Mediated Effects ◽  
Surface Marker Expression ◽  
Extracellular Signal ◽  
Thioredoxin System ◽  
Stromal Cell Derived Factor ◽  
Dependent Growth

ABSTRACT The recruitment and differentiation of circulating stem/progenitor cells (SPCs) in subcutaneous Matrigel in mice was assessed. There were over one million CD34+ SPCs per Matrigel plug 18 h after Matrigel implantation, and including a polymer to elevate the lactate concentration increased the number of SPCs by 3.6-fold. Intricate CD34+ cell-lined channels were linked to the systemic circulation, and lactate accelerated cell differentiation as evaluated based on surface marker expression and cell cycle entry. CD34+ SPCs from lactate-supplemented Matrigel exhibited significantly higher concentrations of thioredoxin 1 (Trx1) and hypoxia-inducible factor 1 (HIF-1) than cells from unsupplemented Matrigel, whereas Trx1 and HIF-1 in CD45+ leukocytes were not elevated by lactate. Results obtained using small inhibitory RNA (siRNA) specific to HIF-1 and mice with conditionally HIF-1 null myeloid cells indicated that SPC recruitment and lactate-mediated effects were dependent on HIF-1. Cells from lactate-supplemented Matrigel had higher concentrations of phosphorylated extracellular signal-regulated kinases 1 and 2, Trx1, Trx reductase (TrxR), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1) than cells from unsupplemented Matrigel. SPC recruitment and protein changes were inhibited by siRNA specific to lactate dehydrogenase, TrxR, or HIF-1 and by oxamate, apocynin, U0126, N-acetylcysteine, dithioerythritol, and antibodies to VEGF or SDF-1. Oxidative stress from lactate metabolism by SPCs accelerated further SPC recruitment and differentiation through Trx1-mediated elevations in HIF-1 levels and the subsequent synthesis of HIF-1-dependent growth factors.

scholarly journals Does Nimodipine, a Selective Calcium Channel Blocker, Impair Chondrocyte Proliferation or Damage Extracellular Matrix Structures?

2019 ◽  
Vol 20 (6) ◽  
pp. 517-524
Author(s):  
Necati Kaplan ◽  
Ibrahim Yilmaz ◽  
Numan Karaarslan ◽  
Yasin E. Kaya ◽  
Duygu Y. Sirin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Active Ingredient ◽  
Cellular Proliferation ◽  
Hypoxia Inducible Factor ◽  
Type Ii Collagen ◽  
Cartilage Tissue ◽  
Control Group ◽  
Chondrocyte Proliferation ◽  
Hypoxia Inducible Factor 1 ◽  
Col2a1 Expression

Background: The study aimed to investigate the effects of the active ingredient, nimodipine, on chondrocyte proliferation and extracellular matrix (ECM) structures in cartilage tissue cells. Methods: Chondrocyte cultures were prepared from tissues resected via surgical operations. Nimodipine was then applied to these cultures and molecular analysis was performed. The data obtained were statistically calculated. Results: Both, the results of the (3-(4,5 dimethylthiazol2-yl)-2,5-diphenyltetrazolium (MTT) assay and the fluorescence microscope analysis [a membrane permeability test carried out with acridine orange/ propidium iodide staining (AO/PI)] confirmed that the active ingredient, nimodipine, negatively affects the cell cultures. Conclusion: Nimodipine was reported to suppress cellular proliferation; chondroadherin (CHAD) and hypoxia-inducible factor-1 alpha (HIF-1α) expression thus decreased by 2.4 and 1.7 times, respectively, at 24 hrs when compared to the control group (p < 0.05). Furthermore, type II collagen (COL2A1) expression was not detected (p<0.05). The risk that a drug prescribed by a clinician in an innocuous manner to treat a patient by relieving the symptoms of a disease may affect the proliferation, differentiation, and viability of other cells and/or tissues at the molecular level, beyond its known side effects or adverse events, should not be forgotten.

Two temporal components within the human pulmonary vascular response to ∼2 h of isocapnic hypoxia

2005 ◽  
Vol 98 (3) ◽  
pp. 1125-1139 ◽  
Author(s):  
Nick P. Talbot ◽  
George M. Balanos ◽  
Keith L. Dorrington ◽  
Peter A. Robbins
Keyword(s):  
Cardiac Output ◽  
Time Course ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Initial Response ◽  
Plateau Phase ◽  
Vascular Response ◽  
Pulmonary Vasoconstriction ◽  
End Tidal ◽  
Underlying Processes

The time course of the pulmonary vascular response to hypoxia in humans has not been fully defined. In this investigation, study A was designed to assess the form of the increase in pulmonary vascular tone at the onset of hypoxia and to determine whether a steady plateau ensues over the following ∼20 min. Twelve volunteers were exposed twice to 5 min of isocapnic euoxia (end-tidal Po2 = 100 Torr), 25 min of isocapnic hypoxia (end-tidal Po2 = 50 Torr), and finally 5 min of isocapnic euoxia. Study B was designed to look for the onset of a slower pulmonary vascular response, and, if possible, to determine a latency for this process. Seven volunteers were exposed to 5 min of isocapnic euoxia, 105 min of isocapnic hypoxia, and finally 10 min of isocapnic euoxia. For both studies, control protocols consisting of isocapnic euoxia were undertaken. Doppler echocardiography was used to measure cardiac output and the maximum tricuspid pressure gradient during systole, and estimates of pulmonary vascular resistance were calculated. For study A, the initial response was well described by a monoexponential process with a time constant of 2.4 ± 0.7 min (mean ± SE). After this, there was a plateau phase lasting at least 20 min. In study B, a second slower phase was identified, with vascular tone beginning to rise again after a latency of 43 ± 5 min. These findings demonstrate the presence of two distinct phases of hypoxic pulmonary vasoconstriction, which may result from two distinct underlying processes.

The effect of repeated intermittent hypoxia on pulmonary vasoconstriction in the newborn

1990 ◽  
Vol 68 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Jaques Belik ◽  
Anna Sienko ◽  
R. Bruce Light
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Vascular Resistance ◽  
Intermittent Hypoxia ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Experimental Animals ◽  
Pulmonary Vasoconstriction ◽  
Air Ventilation ◽  
Experimental Group

The effect of repeated intermittent hypoxia upon the basal pulmonary vascular tone in the newborn period is unknown. We therefore studied the central hemodynamic response to seven repeated intermittent hypoxic challenges in acutely prepared piglets under 2 weeks of age. Catheters were placed in the aorta, pulmonary artery, and atria, and an electromagnetic flow probe was positioned around the main pulmonary artery. Each hypoxic challenge (Fio2 = 0.14) lasted 5 min, and was separated by an equal duration of ventilation with air. Nine control animals were ventilated with air for 90 min, a period of time equivalent to the seven challenges in the experimental group, and subjected to one hypoxic challenge at the end. Hypoxia uniformly induced pulmonary vasoconstriction. Repeated intermittent hypoxic challenges produced a progressive increase in pulmonary artery pressure and vascular resistance, both during air ventilation and hypoxia. For each challenge, the vascular resistance value achieved during hypoxia was directly related to the immediately preceding air ventilation one, and the magnitude of hypoxic pulmonary vasoconstriction, defined as the incremental change in resistance from air to hypoxia, was not different from the first to the last challenge in the experimental group. In the control group the pulmonary vascular tone did not change during the 90 min of air ventilation, and the single hypoxic challenge induced an increase in pulmonary vascular pressure and resistance similar in magnitude to the first challenge in the experimental group. Indomethacin administration to five experimental animals, after the last challenge, reversed the increase in air ventilation pulmonary artery pressure and vascular resistance. Plasma levels of thromboxane B2 and 6-keto-PGF1α were also measured by an enzyme immunoabsorbent assay in half the experimental animals. Surgical stress was associated with a significant rise in both prostaglandin metabolites. Repeated hypoxic challenges led to a further increase in thromboxane B2 and also in the ratio of this metabolite and 6-keto-PGF1α (p < 0.05). The percentage increase in the latter was linearly correlated with the increase in pulmonary arterial pressure and vascular resistance from the first to the last hypoxic challenge. These data indicate that repeated intermittent hypoxia in the newborn pig increases the pulmonary vascular resistance on air ventilation. This phenomenon is possibly related to the release of the potent pulmonary vasoconstrictor thromboxane A2, and may play a role in the pathogenesis of the persistent pulmonary hypertension in human infants who underwent repeated perinatal hypoxic insults.Key words: persistent pulmonary hypertension syndrome, hypoxic pulmonary vasoconstriction, newborn, prostaglandins.

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