Antioxidants Condition Pleiotropic Vascular Responses to Exogenous H(2)O(2): Role of Modulation of Vascular TP Receptors and the Heme Oxygenase System.
Summary of "Antioxidants Condition Pleiotropic Vascular Responses to Exogenous H(2)O(2): Role of Modulation of Vascular TP Receptors and the Heme Oxygenase System."
Abstract Aims: Hydrogen peroxide (H(2)O(2)), a nonradical oxidant, is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported, we examined the hypothesis that the ability of H(2)O(2) to effect vasoconstriction or dilation is conditioned by redox mechanisms and may be modulated by antioxidants. Results: Exogenous H(2)O(2) (0.1-10.0 μM), dose-dependently reduced the internal diameter of rat renal interlobular and 3rd-order mesenteric arteries (p<0.05). This response was obliterated in arteries pretreated with antioxidants, including tempol, pegylated superoxide dismutase (PEG-SOD), butylated hydroxytoluene (BHT), and biliverdin (BV). However, as opposed to tempol or PEG-SOD, BHT & BV, antioxidants targeting radicals downstream of H(2)O(2), also uncovered vasodilation. Innovations: Redox-dependent vasoconstriction to H(2)O(2) was blocked by inhibitors of cyclooxygenase (COX) (indomethacin-10 μM), thromboxane (TP) synthase (CGS13080-10 μM), and TP receptor antagonist (SQ29548-1 μM). However, H(2)O(2) did not increase vascular thromboxane B(2) release; instead, it sensitized the vasculature to a TP agonist, U46619, an effect reversed by PEG-SOD. Antioxidant-conditioned dilatory response to H(2)O(2) was accompanied by enhanced vascular heme oxygenase (HO)-dependent carbon monoxide generation and was abolished by HO inhibitors or by HO-1 & 2 antisense oligodeoxynucleotides treatment of SD rats. Conclusion: These results demonstrate that H(2)O(2) has antioxidant-modifiable pleiotropic vascular effects, where constriction and dilation are brought about in the same vascular segment. H(2)O(2)-induced oxidative stress increases vascular TP sensitivity and predisposes these arterial segments to constrictor prostanoids. Conversely, vasodilation is reliant upon HO-derived products whose synthesis is stimulated only in the presence of antioxidants targeting radicals downstream of H(2)O(2). Antioxid. Redox Signal. 18, 471-480.
Affiliation
1 Department of Pharmacology, New York Medical College , Valhalla, New York.
Journal Details
This article was published in the following journal.
Name: Antioxidants & redox signaling
ISSN: 1557-7716
Pages: 471-80
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22867102
- DOI: http://dx.doi.org/10.1089/ars.2012.4587
Medical and Biotech [MESH] Definitions
Antigenic Modulation
Loss of detectable antigen from the surface of a cell after incubation with antibodies. This is one method in which some tumors escape detection by the immune system. Antigenic modulation of target antigens also reduces the therapeutic effectiveness of treatment by monoclonal antibodies.
Vascular Endothelial Growth Factor Receptor-2
A 200-230-kDa tyrosine kinase receptor for vascular endothelial growth factors found primarily in endothelial and hematopoietic cells and their precursors. VEGFR-2 is important for vascular and hematopoietic development, and mediates almost all endothelial cell responses to VEGF.
Pedunculopontine Tegmental Nucleus
Dense collection of cells in the caudal pontomesencephalic tegmentum known to play a role in the functional organization of the BASAL GANGLIA and in the modulation of the thalamocortical neuronal system.
Vascular Endothelial Growth Factors
A family of angiogenic proteins that are closely-related to VASCULAR ENDOTHELIAL GROWTH FACTOR A. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells.
Vascular Endothelial Growth Factor A
The original member of the family of endothelial cell growth factors referred to as VASCULAR ENDOTHELIAL GROWTH FACTORS. Vascular endothelial growth factor-A was originally isolated from tumor cells and referred to as "tumor angiogenesis factor" and "vascular permeability factor". Although expressed at high levels in certain tumor-derived cells it is produced by a wide variety of cell types. In addition to stimulating vascular growth and vascular permeability it may play a role in stimulating VASODILATION via NITRIC OXIDE-dependent pathways. Alternative splicing of the mRNA for vascular endothelial growth factor A results in several isoforms of the protein being produced.
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