Abstract

PECAM-1 confers the ability of the endothelium to sense temporal gradients in shear stress and strain rate. To test this overall hypothesis, we are taking an entirely integrative approach, using molecular biology, cell biology and biochemistry, vascular and exercise physiology. The first specific aim is to investigate the critical sites involved in PECAM-1's interaction with G.q and eNOS by means of molecular manipulation. The second specific aim will investigate the role of PECAM in the mechanochemical transduction of shear stress, temporal gradients in shear stress, strain and strain rate in endothelial cells from PECAM knockout and wild type mice. The third specific aim will investigate the flow and myogenic responses in isolated arterioles from PECAM knockout and wild type mice. The fourth specific aim will study the role of PECAM-1 in the vascular adaptation to exercise. This investigation will test the comprehensive hypothesis concerning the role of PECAM-1, Gaq and eNOS in mechanochemical transduction of clinically important hemodynamic forces in endothelial cells. If successful it will provide the mechanistic basis on how endothelial cells sense flow in both normal physiology and in vascular disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040696-22
Application #
7390370
Study Section
Special Emphasis Panel (ZRG1-SSS-8 (03))
Program Officer
Srinivas, Pothur R
Project Start
1988-04-01
Project End
2009-08-31
Budget Start
2008-04-01
Budget End
2009-08-31
Support Year
22
Fiscal Year
2008
Total Cost
$431,422
Indirect Cost

  Institution

Name
La Jolla Institute
Department
Type
DUNS #
114215473
City
San Diego
State
CA
Country
United States
Zip Code
92121

  Publications

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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