Role of blood cell-associated AT1 receptors in the microvascular responses to hypercholesterolemia

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. C57B1/6 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.