Nitric oxide specifically inhibits integrin‐mediated platelet adhesion and spreading on collagen

Abstract

To cite this article: Roberts W, Riba R, Homer-Vanniasinkam S, Farndale RW, Naseem KM. Nitric oxide specifically inhibits integrin-mediated platelet adhesion and spreading on collagen. J Thromb Haemost 2008; 6: 2175-85.Summary. Background: Nitric oxide (NO) inhibits platelet adhesion to collagen, although the precise molecular mechanisms underlying this process are unclear. Objectives: Collagenmediated adhesion is a multifaceted event requiring multiple receptors and platelet-derived soluble agonists. We investigated the influence of NO on these processes. Results: S-nitrosoglutathione (GSNO) induced a concentration-dependent inhibition of platelet adhesion to immobilized collagen. Maximal adhesion to collagen required platelet-derived ADP and TxA 2 . GSNO-mediated inhibition was lost in the presence of apyrase and indomethacin, suggesting that NO reduced the availability of, or signaling by, ADP and TxA 2 . Exogenous ADP, but not the TxA 2 analogue U46619, reversed the inhibitory actions of GSNO on adhesion. Under adhesive conditions NO inhibited dense granule secretion but did not influence TxA 2 generation. These data indicated that NO may block signaling by TxA 2 required for dense granule secretion, thereby reducing the availability of ADP. Indeed, we found TxA 2 -mediated activation of PKC was required to drive dense granule secretion, a pathway that was inhibited by NO. Because our data demonstrated that NO only inhibited the activation-dependent component of adhesion, we investigated the effects of NO on individual collagen receptors. GSNO inhibited platelet adhesion and spreading on a 2 b 1 specific peptide ligand GFOGER. In contrast, GSNO did not inhibit GPVI-mediated adhesion to collagen, or adhesion to the GPVI specific ligand, collagen related peptide (CRP). Conclusions: NO targets activationdependent adhesion mediated by a 2 b 1 , possibly by reducing bioavailability of platelet-derived ADP, but has no effect on activation-independent adhesion mediated by GPVI. Thus, NO regulates platelet spreading and stable adhesion to collagen.

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

“…Indeed, the function of the vascular endothelium is significantly impaired during diabetes, a phenomena termed endothelial dysfunction and characterized by the reduced bioavailability of an important endothelial cell mediator, nitric oxide (NO). Such chronic attenuation of endothelial-derived NO release promotes platelet and leukocyte activation and adhesion, compromises endothelial cell barrier integrity, and causes the upregulation of proinflammatory genes (6)(7)(8). Moreover, reduced NO-dependent vasodilation and increased leukocyte adhesion to the endothelium, both of which are hallmarks of endothelial dysfunction, have been observed in patients with diabetes and diabetic animal models (9)(10)(11)(12).…”

Activators, receptors and signal transduction pathways of blood platelets

“…Также NO способен стимулировать фосфорилирование рецепторов к TXA 2 , тем самым предотвращая активацию тромбоцитов TXA 2 [106]. Кроме того, в последнее время было показано, что NO также определенным образом влияет на активацию интегрина a 2 b 1 [107]. Хотя NO оказывает тормозящее действие на агрегацию тромбоцитов при высоких его концентрациях, он скорее стимулирует секрецию гранул, действуя через сGМP-зависимый путь при низких концентрациях (бифазный эффект) in vivo [108].…”

Oxide in hemodialysis patients

“…It is an important messenger molecule involved in many pathological and physiological processes (1). Its physiological role is related to vessel homeostasis via the inhibition of vascular smooth muscle contraction and growth, inhibition of platelet aggregation, and inhibition of white blood cell adhesion to the endothelium (2). NO also plays a role in inflammation and immune responses when generated by the phagocytes during the process of killing bacteria (via DNA damage) (3).…”