Neuregulin-1 Attenuates Neointimal Formation following Vascular Injury and Inhibits the Proliferation of Vascular Smooth Muscle Cells

Abstract

Neuregulin-1 (NRG-1) is expressed in vascular endothelial cells, and its receptors are localized to the underlying smooth muscle cells. However, the role of NRG-1 in vascular function and injury is largely unknown. First, the expression of NRG-1 and its receptors (erbB receptors) was analyzed after balloon injury to the rat carotid artery. NRG-1 and erbB expression levels were low in uninjured vessels; however, NRG-1 and erbB4 were upregulated following injury. We then examined the effect of NRG-1 on neointimal formation following balloon injury. NRG-1 was administered by tail-vein injection prior to injury and every 2 days following injury. Two weeks after injury, NRG-1-treated animals demonstrated a 50% reduction in lesion size compared with controls receiving the vehicle. To examine possible mechanisms for NRG-1 action, we examined its effects on vascular smooth muscle cell (VSMC) function. Rat VSMC cultures were pretreated with NRG-1 for 24 h and then stimulated with platelet-derived growth factor. NRG-1 significantly decreased platelet-derived growth factor-stimulated VSMC proliferation and migration. These findings suggest that NRG-1 may be a novel therapeutic candidate for the treatment of restenosis and atherosclerosis.

Preventive Effects of Heregulin-β 1 on Macrophage Foam Cell Formation and Atherosclerosis

“…Clement et al have shown that heregulin-␤ 1 inhibits platelet-derived growth factor-stimulated VSMC proliferation by suppressing extracellular signalregulated kinase 1/2 phosphorylation. 28 In the present study, the intracellular signaling mechanisms by which heregulin-␤ 1 modulates SR-A, ACAT1, and ABCA1 expression in macrophages remain to be addressed. Further studies are required to determine the signaling molecules and transcription factors concerned.…”

“…9 A recent study showed that endogenous heregulin-␤ 1 and erbB4 are upregulated following balloon injury of rat carotid arteries. 28 Upregulation of heregulin-␤ 1 is regarded as an immediate protective response to inhibit VSMC proliferation and extracellular matrix production after vascular injury. 28 Infusion of exogenous heregulin-␤ 1 into rats attenuates balloon injury-induced neointimal formation by inhibiting VSMC proliferation.…”

“…28 Upregulation of heregulin-␤ 1 is regarded as an immediate protective response to inhibit VSMC proliferation and extracellular matrix production after vascular injury. 28 Infusion of exogenous heregulin-␤ 1 into rats attenuates balloon injury-induced neointimal formation by inhibiting VSMC proliferation. 28 In the present study, the increasing intimal levels of heregulin in the aorta of ApoE Ϫ/Ϫ mice may reflect a protective response to atherosclerosis, comparable to the attempt of macrophages to take up atherogenic oxidized LDL from the extracellular intima.…”

“…However, heregulin-␤ 1 inhibits skin endothelial cell and VSMC proliferation. 28,30 This discrepancy may be attributed to the difference in cell type. Clement et al have shown that heregulin-␤ 1 inhibits platelet-derived growth factor-stimulated VSMC proliferation by suppressing extracellular signalregulated kinase 1/2 phosphorylation.…”

Gene Expression Profile of Blood Cells for the Prediction of Delayed Cerebral Ischemia after Intracranial Aneurysm Rupture: A Pilot Study in Humans

“…NRG1 is upregulated by hypoxic/normoxic preconditioning and increases the endothelial differentiation potential of human bone marrow CD133+ cells [29]. For some authors, NRG1 has an inhibitory effect on neointimal formation after vascular injury and prevents mitogen-induced vascular smooth muscle cell proliferation and migration [30]. …”