Angiotensin II-Induced Mononuclear Leukocyte Interactions with Arteriolar and Venular Endothelium Are Mediated by the Release of Different CC Chemokines

Abstract

Angiotensin II (Ang-II) is associated with atherogenesis and arterial subendothelial mononuclear leukocyte infiltration. We have demonstrated that Ang-II causes the initial attachment of mononuclear cells to the arteriolar endothelium. We now report on the contribution of CC chemokines to this response. Intraperitoneal administration of 1 nM Ang-II induced MCP-1, RANTES, and MIP-1α generation, maximal at 4 h, followed by mononuclear leukocyte recruitment at 8 and 24 h. Using intravital microscopy within the rat mesenteric microcirculation 4 h after exposure to 1 nM Ang-II, arteriolar mononuclear cell adhesion was 80–90% inhibited by pretreatment with Met-RANTES, a CCR1 and CCR5 antagonist, or an anti-MCP-1 antiserum, without affecting the increased endothelial expression of P-selectin and VCAM-1. Conversely, leukocyte interactions with the venular endothelium, although inhibited by Met-RANTES, were little affected by the anti-MCP-1. Using rat whole blood in vitro, Ang-II (100 nM) induced the expression of monocyte CD11b that was inhibited by Met-RANTES but not by anti-MCP-1. Stimulation of human endothelial cells (human umbilical arterial endothelial cells and HUVECs) with 1–1000 nM Ang-II, predominantly acting at its AT1 receptor, induced the release of MCP-1 within 1 h, RANTES within 4 h, and MCP-3 within 24 h. Eotaxin-3, a natural CCR2 antagonist, was released within 1 h and may delay mononuclear cell responses to MCP-1. Therefore, Ang-II-induced mononuclear leukocyte recruitment at arterioles and venules is mediated by the production of different CC chemokines. Thus, Ang-II may be a key molecule in the initial attachment of mononuclear cells to the arterial endothelium in cardiovascular disease states where this event is a characteristic feature.

Anti-Inflammatory Effects of the Activation of the Angiotensin-(1–7) Receptor, Mas, in Experimental Models of Arthritis

“…2 for review). Consistent with the latter finding, blockade of AT 1 , the major receptor mediating the inflammatory actions of Ang II, reduces neutrophil recruitment and cytokine release in models of inflammation (12,37,38). However, to our knowledge, the expression of Mas receptor in periarticular tissues was demonstrated for the first time in the present study.…”

“…In addition to inhibiting neutrophil influx due to the inhibition of local production of chemokines, it was possible that Mas agonists could be directly interfering with the process of leukocyte-endothelial cell interaction, hence preventing their influx. In support of the latter possibility, other studies have found that Ang II via AT 1 receptor stimulated leukocyte-endothelium interactions and increased neutrophil migration in vivo (37,38). In our study, treatment with the Mas receptor agonist AVE 0991 significantly inhibited rolling and cell adhesion of leukocytes to endothelial cells in the joint microvasculature of mice subjected to AIA.…”

“…Such inhibition could account for the local inhibition of neutrophil influx. However, a few studies have shown that components of the RAS may affect leukocyte recruitment directly by affecting leukocyteendothelial cell interactions (37,38). To evaluate whether activation of the Mas receptor would affect leukocyte-endothelium interactions in vivo, we used an intravital microscopy strategy in which AVE 0991 was given to mice much after immunization and challenge but just prior to the intravital procedures (Fig.…”

Angiotensin II AT1 receptor blockade normalizes CD11b+ monocyte production in bone marrow of hypercholesterolemic monkeys

“…The reninangiotensin system (RAS) may play a role in this activation process since hypercholesterolemia upregulates AT 1 receptor expression in a variety of tissues 2 and in vitro stimulation of AT 1 subtype receptors by angiotensin (Ang) II directly increases monocyte CD11b. 3 The suppression of monocyte CD11b by AT 1 receptor blockade in patients with coronary artery disease 4 and in monkeys with hypercholesterolemia-induced atherosclerosis 5 provides additional evidence that the RAS regulates the phenotype of circulating monocytes and their atherogenicity. The anti-inflammatory action of Ang II receptor blockers (ARBs) reflected by diminished CD11b expression may be an important mechanism by which this drug class exerts its anti-atherosclerotic effects independent of blood pressure-lowering.…”

Angiotensin II Type 1 Receptor Blocker Reduces Monocyte Adhesion to Endothelial Cells in Spontaneously Hypertensive Rats

“…Angiotensin II induces endothelial dysfunction and vascular remodeling in several experimental models [12], and is known to promote both mitogenic signals and oxidative stress in the vasculature [13]. These signals result in arterial inflammation, which in turn upregulates monocyte recruitment [11,[14][15][16]. However, it remains unclear, whether inhibition of angiotensin II reduces monocyte adhesion to endothelial cells beyond the effect of simply reducing blood pressure.…”