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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:313.)
© 2006 American Heart Association, Inc.

Vascular Biology

Role of Blood Cell–Associated AT1 Receptors in the Microvascular Responses to Hypercholesterolemia

Thomas Petnehazy; Karen Y. Stokes; Katherine C. Wood; Janice Russell; D. Neil Granger

From the Department of Molecular and Cellular Physiology (T.P., K.Y.S., K.C.W., J.R., D.N.G.), Louisiana State University, Health Sciences Center, Shreveport; and the University Klinik for Pediatric Surgery (T.P.), University of Graz, Austria.

Correspondence to D. Neil Granger, Department of Molecular and Cellular Physiology, Louisiana State University, Health Sciences Center, 1501 E Kings Highway, Shreveport, LA 71130-3932. E-mail dgrang{at}lsuhsc.edu

Objective— Hypercholesterolemia elicits a proinflammatory and prothrombogenic phenotype in the microvasculature that is characterized by activation and adhesion of blood cells. The angiotensin II receptor-1 antagonist Losartan prevents the induction of these responses. The objective of this study was to determine the relative contributions of blood cell-associated versus endothelium-associated AT1a-R to these hypercholesterolemia-induced microvascular alterations.

Methods and Results— Leukocyte adhesion and emigration and platelet adhesion were quantified by intravital microscopy in postcapillary venules. C57Bl/6 mice were placed on a normal (ND) or high-cholesterol (HCD) diet for 2 weeks. AT1a-R bone marrow chimeras that express AT1a-R on the vessel wall but not blood cells and AT1a-R knockouts were placed on HCD. Venular shear rate was comparable in all groups. Platelet and leukocyte adhesion and leukocyte emigration were significantly increased in HCD mice versus ND. Leukocyte recruitment was significantly reduced in the HCD-AT1a-R bone marrow chimera group, whereas platelet adhesion remained at HCD levels. However, in HCD-AT1a-R knockout mice, platelet and leukocyte adhesion were reduced to ND levels.

Conclusions— These data indicate that the platelet-vessel wall adhesion elicited by hypercholesterolemia is mediated by AT1a-R engagement on the endothelial cell rather than the platelet, whereas leukocyte recruitment is mediated by blood cell-associated AT1a-R.

We used AT1a-R–deficient mice and AT1a-R bone marrow chimeras, where blood cells (but not endothelial cells) lacked AT1a-R, to define the contributions of blood cell–associated versus endothelium-associated AT1a-R to hypercholesterolemia-induced microvascular alterations. Endothelium-associated (not platelet-associated) AT1a-R mediated the platelet adhesion, whereas AT1a-R on blood cells modulated the leukocyte recruitment.

Key Words: angtiotensin II type 1 receptor • microcirculation • hypercholesterolemia • platelets • leukocytes

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