The overall goal of this project is to test the prevailing hypothesis that hypertension and arteriosclerosis may be linked through a mechanism that involves oxidative stress. Our working hypothesis is that oxidative stress in hypertension and atherosclerosis acts to induce similar alterations in the expression of specific integrins and extracellular matrix (ECM) proteins that are responsible for changes in vasomotor function and vascular smooth muscle (VSM) phenotype. Our recent studies have established a novel link between VSM and endothelial integrins and the control of vascular tone. In addition, preliminary data indicates that oxidative stress can alter the expression of at least one of the VSM integrins linked to vasomotor activity and an ECM protein that is a ligand for this receptor. These altered integrin/matrix interactions may predispose the arterial wall to development of vascular pathology. This project incorporates a model of renal hypertension and atherogenesis that will be studied at various stages of disease development in large, intermediate and microvascular sized arterial vessels. Assessments will be made of the redox status, integrin and ECM profiles and vascular reactivity to soluble and insoluble integrin-binding ligands. These ligands will include synthetic Arginine-Glycine-Aspartic Acid (RGD) containing peptides and type I collagen and osteopontin, which are up-regulated following vascular injury. Our strategy is combining studies of intact vessels, cellular, biochemical and molecular approaches will provide a powerful approach for testing our hypothesis and systematically integrating our results, The specific aims are:
Aim 1 : Characterize the vasomotor response for large intermediate and small arterial vessels to known integrin-binding peptides, type I collagen and osteopontin at varius stages of development for a rat model of renal hypertension and/or imposed oxidative stress (allylamine treated). Vasoactivity will be correlated with measurements of redox status and integrin/ECM profiles.
Aim 2 : Characterize the vascular redox status and mechanisms leading to the development of oxidative stress in models of renal hypertension and atherogenesis and evaluate the role of NFkappaB as a common signal transduction pathway.
Aim 3. Characterize and evaluate changes in vascular ECM/integrin expression at the gene and protein levels that are associated with renal hypertension or oxidative stress and to define the influence of oxidative stress on extracellular matrix and integrin gene expression. These studies will provide new information that will advance our understanding vascular function in hypertension and atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062863-03
Application #
6390395
Study Section
Special Emphasis Panel (ZHL1-CSR-B (F1))
Program Officer
Barouch, Winifred
Project Start
1999-08-15
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$288,000
Indirect Cost
Name
Texas A&M University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Clark, Catharine G; Sun, Zhe; Meininger, Gerald A et al. (2013) Atomic force microscopy to characterize binding properties of ?7-containing nicotinic acetylcholine receptors on neurokinin-1 receptor-expressing medullary respiratory neurons. Exp Physiol 98:415-24
Zhu, Yi; Qiu, Hongyu; Trzeciakowski, Jerome P et al. (2012) Temporal analysis of vascular smooth muscle cell elasticity and adhesion reveals oscillation waveforms that differ with aging. Aging Cell 11:741-50
Iwatsubo, Kosaku; Bravo, Claudio; Uechi, Masami et al. (2012) Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. Am J Physiol Heart Circ Physiol 302:H2622-8
Qiu, Hongyu; Zhu, Yi; Sun, Zhe et al. (2010) Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res 107:615-9
Sun, Zhe; Martinez-Lemus, Luis A; Hill, Michael A et al. (2008) Extracellular matrix-specific focal adhesions in vascular smooth muscle produce mechanically active adhesion sites. Am J Physiol Cell Physiol 295:C268-78
Chao, Jun-Tzu; Martinez-Lemus, Luis A; Kaufman, Stephen J et al. (2006) Modulation of alpha7-integrin-mediated adhesion and expression by platelet-derived growth factor in vascular smooth muscle cells. Am J Physiol Cell Physiol 290:C972-80
Chowdhury, Mustafa H; Gant, V Alexander; Trache, Andreea et al. (2006) Use of surface-enhanced Raman spectroscopy for the detection of human integrins. J Biomed Opt 11:024004
Partridge, C R; Williams, E S; Barhoumi, R et al. (2005) Novel genomic targets in oxidant-induced vascular injury. J Mol Cell Cardiol 38:983-96
Martinez-Lemus, Luis A; Crow, Tracy; Davis, Michael J et al. (2005) alphavbeta3- and alpha5beta1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles. Am J Physiol Heart Circ Physiol 289:H322-9
Neiger, Jessemy D; Crow, Tracy Y; Partridge, Charles R et al. (2005) Modulation of alpha4 integrin mRNA levels is coupled to deficits in vasomotor function in rat arterioles by allylamine. Life Sci 76:1895-905

Showing the most recent 10 out of 16 publications