It is now increasingly evident that hemodynamic flow has an important role in regulating vessel diameter and caliber, and this is mediated by the endothelial lining of the blood vessel wall. Two functional responses of endothelial cells that are controlled by flow are the release of endothelial-derived relaxing factor (EDRF) and the potent vasoconstrictor and mitogen, endothelin (ET-1). The mechanism of how endothelial cells sense flow is unknown. Furthermore, the responses to pulsatile flow appear to be different than to steady flow. It is known, however, that the signal transducing G-proteins mediate the responses. It is our hypothesis that fluid shear """"""""perturbs"""""""" the cell membrane and/or cytoskeleton, thereby altering the activity of G-proteins and/or associated receptors. To test this hypothesis, purified G-proteins and protein activation will be monitored under various conditions to determine if shear acts on cytoskeleton (actin, microtubule and vimentin filaments) in steady and pulsatile flow stimulation will also be assessed by perturbing each of them and measuring EDRF release. The locus of the """"""""perturbation"""""""" will also be investigated by determining the where in monitoring the location of inositol phospholipid hydrolysis. There are several responses of flow which differ from agonist stimulation in endothelial cells. An important difference is the role of calcium-calmodulin in the activation of EDRF synthase. By using molecular and biochemical techniques to characterize these differences, we may be able to shed light on the mechanism of flow-signal transduction. One of the functions of flow-induced EDRF appears to be regulation of ET-1 release. It is not clear, however, how this regulation occurs. This will be investigated by measuring the effect of EDRF and EDRF-induced cGMP on peptide intermediates of ET-1. By establishing how the fundamental mechanism by which flow stimulates endothelial cells, and its regulation of EDRF and ET-1, we will be able to understand flow-dependent control of vascular diameter and remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL040696-06
Application #
3357983
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1988-04-01
Project End
1997-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Engineering
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Hightower, C Makena; Intaglietta, Marcos (2009) Early iNOS impairment and late eNOS enhancement during reperfusion following 2.49 MHz continuous ultrasound exposure after ischemia. Ultrason Sonochem 16:197-203
Otte, Laura A; Bell, Kelly S; Loufrani, Laurent et al. (2009) Rapid changes in shear stress induce dissociation of a G alpha(q/11)-platelet endothelial cell adhesion molecule-1 complex. J Physiol 587:2365-73
Hightower, C Makena; Intaglietta, Marcos (2007) The use of diagnostic frequency continuous ultrasound to improve microcirculatory function after ischemia-reperfusion injury. Microcirculation 14:571-82
Martini, Judith; Carpentier, Benoit; Negrete, Adolfo Chavez et al. (2005) Paradoxical hypotension following increased hematocrit and blood viscosity. Am J Physiol Heart Circ Physiol 289:H2136-43
Cabrales, Pedro; Tsai, Amy G; Winslow, Robert M et al. (2005) Extreme hemodilution with PEG-hemoglobin vs. PEG-albumin. Am J Physiol Heart Circ Physiol 289:H2392-400
Khalife, Wissam I; Tang, Yi-Da; Kuzman, James A et al. (2005) Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 289:H2409-15
Cabrales, Pedro; Tsai, Amy G; Frangos, John A et al. (2005) Role of endothelial nitric oxide in microvascular oxygen delivery and consumption. Free Radic Biol Med 39:1229-37
Sakai, Hiromi; Cabrales, Pedro; Tsai, Amy G et al. (2005) Oxygen release from low and normal P50 Hb vesicles in transiently occluded arterioles of the hamster window model. Am J Physiol Heart Circ Physiol 288:H2897-903
Winslow, Robert M; Lohman, Jeff; Malavalli, Ashok et al. (2004) Comparison of PEG-modified albumin and hemoglobin in extreme hemodilution in the rat. J Appl Physiol 97:1527-34
Kerger, Heinz; Groth, Gesine; Kalenka, Armin et al. (2003) pO(2) measurements by phosphorescence quenching: characteristics and applications of an automated system. Microvasc Res 65:32-8

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