Published online before print December 11, 2003, doi: 10.1161/01.RES.0000111524.05779.60
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Integrative Physiology |
Cerebral Microvascular Responses to Hypercholesterolemia
Roles of NADPH Oxidase and P-Selectin
From the Departments of Molecular and Cellular Physiology (M.I., K.Y.S., D.N.G.) and Neurosurgery (J.H.Z., A.N.), Louisiana State University Health Sciences Center, Shreveport, La.
Correspondence to D. Neil Granger, PhD, Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. E-mail dgrang{at}lsuhsc.edu
Although hypercholesterolemia is widely accepted as a major risk factor for coronary artery and peripheral vascular diseases, its role in the pathogenesis of stroke is controversial. The objectives of this study were to determine how hypercholesterolemia affects the cerebral microcirculation under resting conditions and after ischemia-reperfusion (I/R). Platelet- and leukocyte-endothelial cell interactions and oxidant production (using the oxidant-sensitive fluorochrome dihydrorhodamine-123) were monitored by intravital videomicroscopy in the cerebral microvasculature of mice placed on either a normal (ND) or cholesterol-enriched diet (HCD). Platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) and leukocytes labeled with rhodamine 6G were seen to roll and firmly adhere, with a corresponding increase in oxidant production, in venules of mice on HCD, but not ND. Immunoneutralization of P-selectin attenuated the platelet- and leukocyte-endothelial cell interactions and the enhanced oxidant production associated with HCD. A GPIIb/IIIa blocking antibody did not alter the blood cell-vessel wall interactions to HCD. Mice deficient in the NADPH oxidase subunit gp91phox exhibited significantly blunted platelet and leukocyte recruitment responses to HCD. Focal I/R also elicited inflammatory and prothrombogenic responses in cerebral venules and these were exaggerated in mice on HCD. These results implicate an oxidant-dependent, P-selectin–mediated mechanism in the blood cell-vessel wall interactions induced by hypercholesterolemia in the brain and demonstrate that the deleterious effects of I/R on the brain are exacerbated by this cardiovascular risk factor.
Key Words: platelet adhesion • leukocyte adhesion • P-selectin • cerebral ischemia • GPIIb/IIIa
This article has been cited by other articles:
 |
|
 |
|
  M. Al-Shabrawey, M. Rojas, T. Sanders, A. Behzadian, A. El-Remessy, M. Bartoli, A. K. Parpia, G. Liou, and R. B. Caldwell Role of NADPH Oxidase in Retinal Vascular Inflammation Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3239 - 3244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Wolfort, K. Y. Stokes, and D. N. Granger CD4+ T lymphocytes mediate hypercholesterolemia-induced endothelial dysfunction via a NAD(P)H oxidase-dependent mechanism Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2619 - H2626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ishikawa, E. Sekizuka, N. Yamaguchi, H. Nakadate, S. Terao, D. N. Granger, and H. Minamitani Angiotensin II type 1 receptor signaling contributes to platelet-leukocyte-endothelial cell interactions in the cerebral microvasculature Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2306 - H2315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. da Cunha, B. Martin-McNulty, J. Vincelette, L. Zhang, J. C. Rutledge, D. W. Wilson, R. Vergona, M. E. Sullivan, and Y.-X. Wang Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice J. Lipid Res., March 1, 2006; 47(3): 476 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Petnehazy, K. Y. Stokes, K. C. Wood, J. Russell, and D. N. Granger Role of Blood Cell-Associated AT1 Receptors in the Microvascular Responses to Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 313 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ishikawa, T. Vowinkel, K. Y. Stokes, T. V. Arumugam, G. Yilmaz, A. Nanda, and D. N. Granger CD40/CD40 Ligand Signaling in Mouse Cerebral Microvasculature After Focal Ischemia/Reperfusion Circulation, April 5, 2005; 111(13): 1690 - 1696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Petnehazy, K. Y. Stokes, J. M. Russell, and D. N. Granger Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules Hypertension, February 1, 2005; 45(2): 209 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-M. Park, S. Cho, K. Frys, G. Racchumi, P. Zhou, J. Anrather, and C. Iadecola Interaction Between Inducible Nitric Oxide Synthase and Poly(ADP-ribose) Polymerase in Focal Ischemic Brain Injury Stroke, December 1, 2004; 35(12): 2896 - 2901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Arumugam, J. W. Salter, J. H. Chidlow, C. M. Ballantyne, C. G. Kevil, and D. N. Granger Contributions of LFA-1 and Mac-1 to brain injury and microvascular dysfunction induced by transient middle cerebral artery occlusion Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2555 - H2560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Li and A. M Shah Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1014 - R1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Krotz, H.-Y. Sohn, and U. Pohl Reactive Oxygen Species: Players in the Platelet Game Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 1988 - 1996. [Abstract] [Full Text] [PDF]
|
|