Overexpression of the P2Y 2 Purinoceptor in Intimal Lesions of the Rat Aorta

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114

Extracellular nucleotides cause a wide range of cellular responses and appear to play a role in the regulation of many vascular functions (1, 2). Vascular cells release nucleotides when exposed to stimuli such as ischemia, hypoxia, and chemical or mechanical stress (3, 4). It also is becoming apparent that extracellular nucleotides can promote the development of a variety of pathologies including disorders of the immune system, and neurodegenerative and vascular diseases (1). Indeed, ATP or UTP induces proliferation and migration of vascular smooth muscle cells, two processes involved in the development of intimal lesions found in atherosclerosis and post-angioplasty restenosis. The biological effects of extracellular nucleotides are mediated through activation of P1 and P2 purinergic receptors. P1 receptors are responsive to adenosine, whereas P2 receptors are activated by a variety of nucleotides including ATP and UTP (5, 6). The P2 receptors are subdivided into two distinct categories, the metabotropic Gprotein-coupled (P2Y) receptors and the ionotropic ligandgated channel (P2X) receptors (6, 7). Vascular cells have been shown to express metabotropic P2Y and ionotropic P2X receptors (5, 8). It has been reported that P2Y 2 receptors are upregulated in cells of rat intimal lesions following balloon angioplasty (9). Our recent studies showed that placement of a silicone collar around the rabbit carotid artery promoted upregulation of P2Y 2 receptors in vascular smooth muscle cells and endothelium (10). Subsequently, local infusion of UTP was shown to stimulate intimal hyperplasia and increase intimal monocyte infiltration (10), suggesting a role for P2Y 2 receptors in the recruitment of blood monocytes leading to inflammation in atherosclerosis.Monocyte recruitment into the vessel wall is a complex process that includes cell rolling, firm attachment, and directed migration. It is now becoming evident that adhesion molecules such as VCAM-1 play an important role in leukocyte adherence to vascular endothelial cells (11,12). VCAM-1 expression is induced or up-regulated by proinflammatory cytokines such as TNF-␣ 1 and interleukin 1-␤ on cellular components of the arterial wall including endothelial cells, smooth muscle cells, and fibroblasts (13-15). ATP and UTP have been shown to induce cell-cell adhesion in a monocyte/macrophage lineage and neutrophil adherence to an endothelial cell monolayer (16,17), raising the possibility that released ATP and UTP could induce endothelial cell activation by an autocrine/paracrine mechanism to regulate leukocyte adherence.

mentioning

confidence: 66%

The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells

Seye

Jain

et al. 2003

107

114

“…The P2Y 2 R is up-regulated in a variety of tissues in response to injury or stress, including the vasculature (33). We have shown that stress-activated up-regulation of P2Y 2 Rs in vascular endothelium in vivo increases the expression of adhesion molecules, monocyte adherence, and transendothelial migration (34,35), suggesting that P2Y 2 Rs for cytokine-like nucleotides play a role in endothelial-dependent inflammation.…”

mentioning

confidence: 87%

P2Y2 Receptor-mediated Lymphotoxin-α Secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells

Seye

Ağca

Derbigny

2012

Background: Lymphotoxin-␣ (LTA) is involved in the pathogenesis of atherosclerosis. Results: The P2Y 2 nucleotide receptor (P2Y 2 R) recruits filamin A to activate Rho signaling upstream of LTA secretion leading to intercellular cell adhesion molecule-1 expression. Conclusion: P2Y 2 R regulates LTA gene activation and secretion in vascular smooth muscle cells. Significance: This suggests that P2Y 2 R is an important regulator of vascular inflammation.

“…Although the P2Y 2 R is normally expressed in monocytes, neutrophils, and other immune cells (13), recent studies have shown that the P2Y 2 R is up-regulated in epithelial and vascular tissue in response to injury or stress (14). Upon activation, the P2Y 2 R mediates a variety of biological functions, including mitogenesis, angiogenesis, vasodilatation, chemotaxis, and inflammation (15,16).…”

mentioning

confidence: 99%

The P2Y2 Nucleotide Receptor Interacts with αv Integrins to Activate Go and Induce Cell Migration

Bagchi

Liao

González

et al. 2005

100

159

Extracellular ATP and UTP induce chemotaxis, or directed cell migration, by stimulating the G protein-coupled P2Y 2 nucleotide receptor (P2Y 2 R). Previously, we found that an arginine-glycineaspartic acid (RGD) integrin binding domain in the P2Y 2 R enables this receptor to interact selectively with ␣ v ␤ 3 and ␣ V ␤ 5 integrins, an interaction that is prevented by mutation of the RGD sequence to arginine-glycine-glutamic acid (RGE) (Erb, L., Liu, J., Ockerhausen, J., Kong, Q., Garrad, R. C., Griffin, K., Neal, C., Krugh, B. Chemotaxis is the movement of a cell in response to a chemical gradient and is required for many physiological events, including embryonic development, immune system function, and wound healing (2-4). The process of chemotaxis is also important for understanding diseases that result from abnormal cell migration, such as chronic inflammation, atherosclerosis, and cancer metastasis. To migrate, cells must establish dynamic and highly regulated adhesive interactions with the extracellular matrix, which are mediated by integrin receptors (3). For example, recent studies have shown that ␣ v integrins play an important role in controlling cell adhesion, spreading, and motility in several cell types, including human vascular smooth muscle cells and pancreatic beta cells (5, 6). Upon activation, many types of integrin receptors cluster together and recruit a host of cytoskeletal and cytoplasmic proteins into specialized adhesive structures called focal adhesions. These focal adhesion complexes not only serve as a physical link between the extracellular and intracellular matrix but also are important sites of signal transduction for integrins and many other types of receptors that mediate cell migration (7). Chemotaxis also requires a cell to assume a polarized morphology that is controlled by cell surface receptors that activate the Rho family of GTPases, including Cdc42, Rac, and Rho (8, 9). Upon activation of a chemoattractant receptor, Cdc42 and Rac localize at the leading edge of a cell and control directional movement and the formation of lamellipodia containing highly branched actin filaments, respectively (8). Rho localizes at the rear and sides of a cell and controls the formation of contractile actin-myosin stress fibers (10). Together, these GTPases promote cell migration toward a chemoattractant by mediating extension of the actin cytoskeleton at the front edge of the cell and retraction of the cytoskeleton at the rear edge of the cell.Recent studies have shown that G protein-coupled receptors (GPCRs) 2 regulate Rac and Rac-dependent lamellipodia formation by activating the G i/o family of heterotrimeric G proteins, whereas activation of Rho and Rho-dependent stress fiber formation are controlled by the G 12/13 family (10). Furthermore, studies have shown that the ␤␥ subunits of G i/o are responsible for activation of Rac guanine nucleotide exchange factors (RacGEFs) that, in turn, activate Rac, whereas the ␣ subunits of G 12/13 are responsible for activation of RhoGEFs (8,11).The P2Y 2 ...