Ang ii effects on leukocytes cell adhesion and chemotaxis in the vasculature

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A fundamental process in inflammation is extravasation or recruitment of leukocytes from the vascular lumen to the interstitial tissue (9). This phenomenon involves three basic steps: (1) cell rolling, (2) cell adhesion, and (3) transendothelial migration and chemotaxis (movement toward chemotactic stimuli) (Fig. 2).

Adhesion and transendothelial migration of leukocytes into the vessel wall involve sequential interaction of distinct receptors on the surface of leukocytes and endothelial cells. Cellular adhesion molecules, especially members of the selectin family and immunoglobulin superfamily, are involved in leukocyte recruitment to sites of inflammation. Selectins, which are lectin-like molecules expressed on leukocytes (L-selectin), endothelial cells (E-selectin, P-selectin), and platelets (P-selectin), mediate initial contact between circulating leukocytes and vascular endothelium (42,43). Selectins stimulate leukocyte rolling on endothelial cells and promote platelet-leukocyte aggregation. P-selectin is stored in specific granules present in platelets (a-granules) and endothelial cells (Weibel-Palade bodies) from which it can be rapidly recruited to the cell surface after stimulation (44). Rolling leukocytes encounter activated stimuli that trigger activation-dependent adhesion

Weibel Palade Bodies Lymphatic

Fig. 2. Ang Il-mediated processes in vascular leukocyte recruitment. Normally, leukocytes and endothelial cells do not interact. In physiological conditions, leukocytes possess inactive integrins and selectin-binding sites (ligands), but these are unbound, as endothelial cells do not express selectins. Following a pathogenic stimulus, such as increased Ang II levels, endothelial cells are activated and selectin-binding sites are expressed. This results in leukocyte-endothelial cell interaction through weak adhesion (low affinity binding), followed by leukocyte rolling along the endothelium. Subsequent leukocyte activation promotes leukocyte integrins to bind with Ig-supergene family glycoproteins, including ICAM-1 and VCAM-1, resulting in firm adhesion. This is followed by transendothelial migration, which is facilitated by additional Ig-supergene family member expression, including endothelial PECAM-1. Ang II further contributes to the inflammatory process by stimulating synthesis of cytokines, chemokines, and growth factors by VSMCs. CAM, cell adhesion molecules; CTGF, connective tissue growth factor; ICAM-1, intercellular cell adhesion molecule, MCP-1, monocyte chemoattractant protein-1; PECAM, platelet-endothelial cell adhesion molecule; PMN, polymorphonuclear leukocytes; TGF-P, transforming growth factor-P; VCAM, vascular cell adhesion molecule.

Fig. 2. Ang Il-mediated processes in vascular leukocyte recruitment. Normally, leukocytes and endothelial cells do not interact. In physiological conditions, leukocytes possess inactive integrins and selectin-binding sites (ligands), but these are unbound, as endothelial cells do not express selectins. Following a pathogenic stimulus, such as increased Ang II levels, endothelial cells are activated and selectin-binding sites are expressed. This results in leukocyte-endothelial cell interaction through weak adhesion (low affinity binding), followed by leukocyte rolling along the endothelium. Subsequent leukocyte activation promotes leukocyte integrins to bind with Ig-supergene family glycoproteins, including ICAM-1 and VCAM-1, resulting in firm adhesion. This is followed by transendothelial migration, which is facilitated by additional Ig-supergene family member expression, including endothelial PECAM-1. Ang II further contributes to the inflammatory process by stimulating synthesis of cytokines, chemokines, and growth factors by VSMCs. CAM, cell adhesion molecules; CTGF, connective tissue growth factor; ICAM-1, intercellular cell adhesion molecule, MCP-1, monocyte chemoattractant protein-1; PECAM, platelet-endothelial cell adhesion molecule; PMN, polymorphonuclear leukocytes; TGF-P, transforming growth factor-P; VCAM, vascular cell adhesion molecule.

necessary for integrin-mediated arrest. The integrin family includes heterodimeric proteins composed of noncovalently linked a and P subunits. To date at least 15 a- and 8 ^-chains have been identified. Ligand specificity of integrins is based on the a-subunit and comprises two groups: extracellular matrix proteins and cell surface molecules of the immunoglobulin supergene family. Extracellular matrix proteins of importance include fibronectin, thrombospondin, vitronectin, and fibrinogen (44). Important Ig-supergene family members include: intercellular cell adhesion molecules-1 and -2 (ICAM-1, ICAM-2), which bind CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1); vascular cell adhesion molecule-1 (VCAM-1), which binds VLA-4, platelet-endothelial cell adhesion molecule-1 (PECAM-1); and the mucosal address in cell adhesion molecule-2 (MAsCAM-1). ICAM-1 is expressed mainly on endothelial cells (45). VCAM-1, which exhibits low expression on unstimulated endothelial cells, is upregu-lated by cytokines, and mediates adhesion of lymphocytes and monocytes in inflamed vascular beds (44). PECAM-1 is constitutively expressed on platelets, leukocytes, and endothelial cells (46), and MAdCAM-1 is mainly expressed on mucosal endothelial venules (47).

Establishment of an adhesive interaction between endothelial cells and circulating leukocytes involves movement from flowing blood toward the vessel wall (44). Selectins, particularly L-selectin and their ligands, mediate initial weak (low-affinity) adhesive interactions manifested as leukocyte rolling (48). Rolling leukocytes are exposed to low concentrations of chemoattractants or inflammatory mediators resulting in leukocyte activation, which induces leukocyte integrins to bind with Ig-supergene family glyco-proteins, such as ICAM-1 and VCAM-1, permitting firm adhesion. This is associated with downregulation (shedding) of L-selectin (44). Transendothelial migration is mediated by additional Ig-supergene family members, like PECAM-1 and occurs when adherent leukocytes move toward the endothelial cell-cell junctions. During this process, the cell steadily establishes new adhesive contacts at the migration pole, while reducing adhesive interactions at the tail. Leukocytes then migrate into tissues by a chemoattractant gradient. Chemokines are a superfamily of small proteins with chemoattractant properties for specific types of leukocytes. In general, CXC chemokines (a-subfamily) play a role in acute inflammation through neutrophil activation, whereas CC chemokines (^-subfamily) are involved in chronic inflammation through monocytes and lymphocytes (49). Many Ang II-dependent forms of cardiovascular disease, including atherosclerosis, hypertension, cardiac failure, and diabetes, are characterized by vascular monocyte-macrophage infiltration (49-51).

Ang II regulates multiple steps in leukocyte recruitment into the vessel wall. It stimulates production of many pro-inflammatory molecules (Table 1), enhances adhesion of monocytes-neutrophils to endothelial cells by influencing cell adhesion molecules, and promotes transendothelial migration through cytokines and chemokines (51). These effects appear to be independent of pressor actions. Intravital microscopy of rat mesenteric postcapillary venules demonstrated that Ang II infusion increases leukocyte rolling, adhesion, and migration without any vasoconstrictor activity (52). Both ATjR and AT2R appear to play a role in this process, because Ang II-induced effects were abolished by the combination therapy of AT1R and AT2R antagonists (52). In endothelial cells, Ang II upregulates expression of VCAM-1, ICAM-1, and E-selectin through pathways involving ROS (53-55). In VSMCs, Ang II stimulates production of VCAM-1, chemokine monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6, IL-8, and osteopontin in a time- and dose-dependent manner (56-59). These effects are mediated via ATjR and involve RhoA-dependent and redox-sensitive processes (57).

IL-6, a 26-kDa glycoprotein, is a pro-inflammatory cytokine that induces synthesis of acute phase proteins, such as C-reactive protein (CRP), cytokines, and growth factors (60,61). It also activates platelets, has procoagulant activity, and is mitogenic for VSMCs (60-62). IL-8, also called CXCL8 because of a potent neutrophil chemotactic factor (63), induces VSMC proliferation and migration (64). MCP-1 is a small (8-10 kDa) CC type chemokine that specifically attracts monocytes and memory T lymphocytes

Table 1

Summary of Cytokines, Chemokines, Growth Factors, and Other Pro-Inflammatory Mediators Synthesized in Response to Ang II Stimulation

Cytokines

Chemokines

- RANTES

Growth factors

Other immune modulators

- Tissue factor

Abbreviations. bFGF, basic fibroblast growth factor; CTGF, connective tissue growth factor; EGF, epidermal growth factor; ET-1, endothelin-1; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN, interferon; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MIP, macrophage inflammatory protein; PDGF, platelet-derived growth factor; RANTES, regulated on activation, normal T cell expressed and secreted; TGF-P, transforming growth factor-P; TNF-a, tumor necrosis factor a; VEGF, vascular endothelial cell growth factor.

expressing the CC chemokine receptor 2 (CCR2). MCP-1 functions locally in the vessel wall by establishing a chemical gradient to attract adherent monocytes and T-lymphocytes. It is among the most important chemokines regulating migration and infiltration of monocytes-macrophages in the vessel wall (65) and has been implicated to play an essential role in hypertension-induced vascular inflammation and remodeling (66). MCP-1-CCR2 interactions are important in atherosclerosis, because hyperlipidemic-atherosclerotic-prone mice, made genetically deficient in MCP-1 or CCR2, exhibit decreased vascular macrophages with fewer atherosclerotic plaques than control counterparts (67,68). MCP-1-CCR2 is also important in vascular remodeling in Ang II-induced hypertension (69). Osteopontin is a macrophage chemotactic and adhesion molecule, and has been associated with monocyte-macrophage infiltration in atherosclerosis and vascular remodeling with Ang II-mediated hypertension (59). The capacity of Ang II to stimulate regulated expression of adhesion molecules, cytokines, and chemokines promotes recruitment of mononuclear leukocytes into the vessel wall and contributes to the pro-inflammatory properties of this peptide.

Direct Ang II vascular inflammatory effects have also been demonstrated in studies in vivo. Ang II infusion increases expression of vascular ICAM-1 and VCAM-1 through ATj receptors. These processes occur independently of blood pressure changes and involve activation of redox-dependent, mitogen-activated protein (MAP) kinase-regulated pathways (9). To confirm a role of endogenous Ang II in vascular inflammation, studies in apoE-/- mice treated with irbesartan decreased MCP-1 expression in atherosclerotic lesions (70). In hyperlipidemic rabbits, losartan reduced aortic intimal proliferation and induced a significant reduction in expression of P-selectin and MCP-1 (71). Moreover, recent studies from our laboratory demonstrated that the mice lacking macrophage colony-stimulating factor (m-CSF) developed less endothelial dysfunction, vascular remodeling and oxidative stress induced by Ang II than wildtype littermates, further supporting a critical role of pro-inflammatory mediators in Ang II-induced vascular injury (72). In human studies, irbesartan reduced serum levels of VCAM-1 and tumor necrosis factor (TNF)-a in patients with premature atherosclerosis (73); and in hypertensive patients, candesartan decreased plasma levels of MCP-1, TNF-a, and plasminogen activator inhibitor type 1 (PAI-1) (74). In atherosclerotic plaques and in atherectomy specimens of patients with unstable angina, IL-6 and Ang II colocalized with macrophages, further suggesting a role of local Ang II in the recruitment of macrophages in atherogenesis (75). Also, in patients with cardiovascular disease, plasma elevation of MCP-1 was reduced by ACE inhibitors and ATjR blockers (76).

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