application) The hypertensive syndrome is accompanied by a broad range of microvascular dysfunctions. The mechanisms responsible for development of cardiovascular complications in hypertension, however, have remained speculative. The applicant's hypothesis is that in addition to the definitive elevation of the blood pressure a key feature of hypertension is a shift in free radical formation at the tissue level which involves an adrenal/renal pathway. An oxidative stress on one hand leads to elevation of the arteriolar resistance while on the other hand it triggers a multitude of pathophysiological consequence, especially at the level of the microcirculation. Introduction of advanced microvascular techniques has enabled the investigators to identify higher levels of free radical production in-vivo in several models of hypertension together with a shift in the state of activation and interaction of cells in the circulation. The objective of this study is to investigate the mechanisms for the enhanced free radical production and outline its consequences for adjustments of microvascular function. In specific terms, the investigators propose to examine (I) the role of adrenal glucocorticoids and specific oxidases in free radical production, (II) mechanisms by which cell death, including apoptosis, are induced by oxidative stress relative to microvascular rarefaction (a loss of the smallest terminal arterioles and selected capillaries) and its modulation through the involvement of adrenal glucocorticoids, free radical production, and nitric oxide suppression, (III) the modification in the shear stress response of circulating leukocytes and endothelial cells in hypertensives as a consequence of glucocorticoids, and (IV) the basis for the reduced capacity of circulating leukocytes in hypertensives to respond to chemotactic stimuli, reduced adhesion to microvascular endothelium and the consequences for the migratory response. Several well-documented hypertensive models (spontaneously hypertensive rat, Dahl genetic salt-dependent hypertensive model, nitric oxide synthase gene knockout mouse) will be examined in a specific context in order to bring to light common pathophysiological pathways which undermine the microcirculation in various forms of hypertension. Such a program will serve to clarify the pathogenesis of hypertension and is expected to stimulate the design of novel approaches for interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL010881-33
Application #
2901017
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1978-09-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
33
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Mazor, Rafi; Schmid-Schönbein, Geert W (2015) Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion. Biorheology 52:337-52
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Duansak, Naphatsanan; Schmid-Schönbein, Geert W (2013) The oxygen free radicals control MMP-9 and transcription factors expression in the spontaneously hypertensive rat. Microvasc Res 90:154-61
Friese, Ryan S; Altshuler, Angelina E; Zhang, Kuixing et al. (2013) MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension. Hum Mol Genet 22:3624-40
Mazor, Rafi; Alsaigh, Tom; Shaked, Helena et al. (2013) Matrix metalloproteinase-1-mediated up-regulation of vascular endothelial growth factor-2 in endothelial cells. J Biol Chem 288:598-607
Altshuler, Angelina E; Morgan, Mary J; Chien, Shu et al. (2012) Proteolytic Activity Attenuates the Response of Endothelial Cells to Fluid Shear Stress. Cell Mol Bioeng 5:82-91
Schmid-Schönbein, Geert W (2012) An emerging role of degrading proteinases in hypertension and the metabolic syndrome: autodigestion and receptor cleavage. Curr Hypertens Rep 14:88-96
Chen, Angela Y; Ha, Jessica N; Delano, Frank A et al. (2012) Receptor cleavage and P-selectin-dependent reduction of leukocyte adhesion in the spontaneously hypertensive rat. J Leukoc Biol 92:183-94
Schmid-Schonbein, Geert W (2012) Nitric oxide (NO) side of lymphatic flow and immune surveillance. Proc Natl Acad Sci U S A 109:3-4

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