Vascular effects of thrombin: Involvement of NOR-1 in thrombin-induced mitogenic stimulus in vascular cells

Abstract

Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor recently involved in the onset and development of atherosclerosis. NOR-1 is induced in a cell-specific manner by extracellular stimuli. NOR-1 is overexpressed in human atherosclerotic plaques and in porcine arteries subjected to angioplasty, is induced by growth factors in vascular cells and it has been involved in cell migration and proliferation. This article examines the mechanisms that regulate NOR-1 in vascular cells and the effects of NOR-1 knockdown on cell growth induced by mitogens, in particular thrombin. Mitogenic stimuli upregulates NOR-1 in endothelial cells (ECs) through multiple pathways, including increase of cytosolic calcium, activation of protein kinase C, mitogen-activated protein kinase (MAPK) (ERK1/2 and p38 MAPK) and downstream activation of cAMP response element binding protein (CREB). Inhibition of protease-activated receptor-1 (PAR-1) abolished thrombin-induced NOR-1 up-regulation and DNA synthesis. NOR-1 knockdown reduces DNA synthesis and EC re-growth in an in vitro model of wound repair. NOR-1 could be regarded as a new target to prevent endothelial effects triggered by thrombin and other mitogens.