Hypertension is associated with a significantly increased risk for vascular lesions, microvascular complications and end organ failure. Our objective is to explore in experimental models of arterial hypertension basic mechanisms that lead to inflammation and tissue injury at the microvascular level. Our previous results indicate a significant enhancement of microvascular oxidative stress in several models of hypertension. We hypothesize that hypertensives have enhanced levels of microcirculatory apoptosis with arteriolar and capillary rarefaction, a shift in the expression of enzyme profiles producing reactive oxygen species and an abnormal leukocyte-endothelial cell membrane interaction.
Our Specific Aims are (a) to examine in-vivo in the microcirculation of selected tissues the mechanisms of apoptosis in endothelial cells and adjacent parenchymal cells as basis for microvascular rarefaction; (b) to identify the mechanisms for the enhanced oxidative stress in hypertensives and its influence on apoptosis in the microcirculation; and (c) to examine the molecular basis for abnormal adhesion of leukocytes to microvascular endothelium in hypertension and its impact on apoptosis in form of membrane adhesion molecule expression and targeted blockade of leukocyte adhesion molecules. The studies will be carried out within the context of a complete microcirculation, including high and low pressure regions, and identify pressure and non-pressure mediate organ injury mechanisms. We will utilize state-of-the-art digital fluorescent intravital microscopy to generate in-vivo records of apoptosis in microvessels. We will exploit recently developed techniques to display mRNA and protein levels within a microvascular network in order to uncover mechanisms of inflammation that promote apoptosis. The hypertensive state in the spontaneously hypertensive rat will be controlled by depletion and supplementation of adrenal hormones and in the Dahl hypertensive rats by dietary salt enhancement. These studies serve to delineate mechanisms for the expression of key inflammatory mediators in hypertensive microvessels as a basis for development of new interventions against the injurious aspects of this syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL010881-38
Application #
6858719
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
1978-09-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
38
Fiscal Year
2005
Total Cost
$266,000
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Akenhead, Michael L; Fukuda, Shunichi; Schmid-Schönbein, Geert W et al. (2017) Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion. J Leukoc Biol 102:117-126
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
Santamaria, Marco H; Chen, Angela Y; Chow, Jason et al. (2014) Cleavage and reduced CD36 ectodomain density on heart and spleen macrophages in the spontaneously hypertensive rat. Microvasc Res 95:131-42
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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