In the United States, stroke is the third leading cause of death and hypertension is a major risk factor for the severity and occurrence of stroke. Physiologically, angiotensin II (Ang II) is important in regulating blood pressure and fluid homeostasis. During stroke there is a disruption of the blood-brain barrier (BBB), which leads to changes in tight junction proteins (occludin, claudin, ZO-1, ZO-2) and cerebral vasogenic edema. However, the cellular mechanisms leading to this disruption are not well known. Hypoxia (associated with stroke) increases BBB permeability by altering the tight junction proteins (occludin, claudin, ZO-1, ZO-2), and this change in BBB permeability has been shown to involve nitric oxide and changes in intracellular Ca 2+. Ang II, acting via the Ang II type I receptor, has also been shown to cause increases in BBB permeability. However, the molecular mechanisms behind these effects are unknown. Classic Ang II-mediated responses utilize PKC (alpha, beta-I ,beta-II, gamma) and PKC can modify the tight junctions. Recently, it has been demonstrated that hypoxia activates PKC in BBB endothelial cells. The hypothesis of this proposal is that upregulation of intracellular mechanisms by Ang II in endothelial cells of the BBB alters cell permeability and potentiates changes in BBB paracellular permeability due to hypoxic insult. The goal is to investigate the effects of Ang II and hypoxia on PKC(alpha, beta-I, beta-II, gamma) expression and activity and its effects on tight junctions and BBB permeability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32NS049894-03
Application #
7089964
Study Section
Special Emphasis Panel (ZRG1-F01 (20))
Program Officer
Jacobs, Tom P
Project Start
2004-07-05
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$50,428
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Fleegal-DeMotta, Melissa A; Doghu, Shinya; Banks, William A (2009) Angiotensin II modulates BBB permeability via activation of the AT(1) receptor in brain endothelial cells. J Cereb Blood Flow Metab 29:640-7
Fleegal, Melissa A; Hom, Sharon; Borg, Lindsay K et al. (2005) Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation. Am J Physiol Heart Circ Physiol 289:H2012-9