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

Abstract

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. Key Words: angtiotensin II type 1 receptor Ⅲ microcirculation Ⅲ hypercholesterolemia Ⅲ platelets Ⅲ leukocytes W hereas the renin-angiotensin system has long been recognized for its contribution to the pathogenesis of hypertension, recent evidence implicates this regulatory pathway in a variety of other cardiovascular diseases, including atherosclerosis, diabetic vasculopathy, stroke, and myocardial infarction. 1-9 The renin-angiotensin system has also been implicated as a mediator of the deleterious consequences of the known risk factors for cardiovascular disease. For example, AT1-receptor (AT1-R) activation appears to play a major role in the development of the impaired endotheliumdependent vasodilation that is associated with hypercholesterolemia. 10 Angiotensin II can invoke microvascular alterations, including oxidative stress and the adhesion of leukocytes and platelets in postcapillary venules, by acting through AT1-R. 11,12 We have reported recently that the AT1-R antagonist Losartan attenuates the proinflammatory and prothrombogenic effects of hypercholesterolemia in the microvasculature, suggesting that AT1-R engagement on circulating blood cells and/or vascular endothelium is required for these responses. 13 Although the Losartan treatment studies provide circumstantial evidence that indicates a differential responsiveness of platelets, leukocytes, and endothelial cells to AT1-R activation, the experimental strategy used to date cannot definitively resolve the relative contributions of AT1-R on the different cell types to the overall blood cell ...

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

“…Based on a study in the aorta of hyperlipidemic rabbits where AT1-R blockade abrogated vascular superoxide generation from NADH oxidase [9], and previous findings in our model that AT1-R activation mediates the leukocyte adhesion and oxidative stress in postcapillary venules [36] it is conceivable that the vascular and perhaps leukocyte NAD(P)H oxidase is activated through an AT1-R receptor-dependent pathway. Although platelet superoxide release can be stimulated by angiotensin II acting though AT1-R activation [37], platelet AT1-R does not appear to participate in the thrombogenic responses in our model [38]. Consequently, the activation of platelet NAD(P)H oxidase may involve an alternative pathway such as CD40L [39], which has also been implicated in hypercholesterolemia-induced inflammation [40,41].…”

Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan

“…Angiotensin-dependent inflammatory mechanisms have also been implicated in hypercholesterolemia-associated inflammation (38,39) and small, but increased plasma levels of cholesterol have been found in both postmenopausal women and ovariectomized rats. First, it is noteworthy that the levels of plasma cholesterol are in the normal range for healthy postmenopausal women.…”

Oxidative Stress in Mononuclear Cells Plays a Dominant Role in Their Adhesion to Mouse Femoral Artery After Injury

“…We further tried to define the specific cell populations responsible for the mechanical injury-induced leukocyte recruitment and its blockade by olmesartan. Despite its importance in the vascular wall, the oxidative stress in circulating MNCs had not been carefully studied until recent observation of the microvasculature of hypercholesterolemic mice, 12 in which the importance of the Ang II type 1 receptor on leukocytes was addressed for the first time. Indeed, although MNCs from injured mice exhibited significant adhesion to the recipient injured artery, MNCs taken from mice without wire injury failed to adhere to the injured artery ( Figures 4B and 4C), suggesting a dominant role of MNCs in leukocyte recruitment to the femoral artery after injury.…”

“…9,10 The anti-inflammatory effect of ARB has been demonstrated in the microvasculature of the same mouse model. 11 Later, Petnehazy et al 12 reported that, in the atherosclerosis model, the leukocyte-associated but not vasculature-associated Ang II signal plays a dominant role in leukocyte recruitment in the microvasculature, indicating a previously unrecognized role of Ang II-dependent oxidative stress in leukocytes during atherosclerosis. In contrast, limited information is available regarding the role of leukocytes in their recruitment to the mechanically injured artery in vivo.…”