Interleukin-1β and Signaling of Interleukin-1 in Vascular Wall and Circulating Cells Modulates the Extent of Neointima Formation in Mice

Chamberlain, Janet; Evans, David B.; King, Andrea R; Dewberry, Rachael; Dower, Steven K.; Crossman, David C.; Francis, Sheila E.

doi:10.2353/ajpath.2006.051054

Cited by 109 publications

(81 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to identify the hematopoietic cells within the neointima, we analyzed carotid artery cross sections utilizing specific cell surface antigens for the presence of lymphocytes, mast cells, and macrophages. Lymphocytes, mast cells, and macrophages are all inflammatory cells that secrete growth factors and cytokines that have been implicated in neointima formation (25)(26)(27). Further, our group has demonstrated that neurofibromin is a critical regulator of Ras activation in both lymphocytes and mast cells in vitro and in vivo (14,28).…”

Section: Resultsmentioning

confidence: 99%

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Lasater¹,

Li²,

Bessler³

et al. 2010

J. Clin. Invest.

View full text Add to dashboard Cite

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1 +/-mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1 +/-mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions. IntroductionNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from mutations in the tumor suppressor gene NF1 (1). Neurofibromin, the protein product of NF1, functions as a p21 Ras (Ras) GTPase-activating protein (GAP) to negatively regulate Ras activity (2). More than 240 different mutations have been described within the NF1 gene, all of which result in little or no protein product (3). While loss of heterozygosity has been described in primary tumor samples (4), the germline mutations that cause NF1 affect only 1 copy of the NF1 gene. Haploinsufficiency of NF1 results in disease with complete penetrance and a range of clinical complications.The most common clinical manifestations of NF1 include dermal and plexiform neurofibromas, learning deficits, and skeletal abnormalities. Vascular disease associated with NF1 is an underrecognized complication that results in increased morbidity and mortality, particularly among younger patients (5, 6). In 2001, an analysis of 3,253 death certificates of persons with NF1 indicated that the median age of death for NF1 patients was 15 years lower that of the general population (6). In this report, a diagnosis suggestive of NF1 vasculopathy was listed 7.2 times more often than expected among NF1 patients less than 30 years old at time of death and 2.2 times more often than expected among patients 30-40 years old at the time of death (6). Another study demonstrated that 2.5% of children with NF1 who had undergone brain MRI were found to have cerebrovascular system abnormalities including narrowed vessels, moyamoya, va...

show abstract

Section: Resultsmentioning

confidence: 99%

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Lasater¹,

Li²,

Bessler³

et al. 2010

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…2) provides a new physiologic indicator for the inflammatory response evidenced by neointimal formation. IL-1β is not only a marker but rather a mediator of SMC proliferation [18], that is important in neointimal formation [19]. However, the correlation was not precise since there was no marked reduction in IL-1β arterial levels in the preconditioned group to correlate with the significant reduction in neointimal formation observed in this group.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

et al. 2008

View full text Add to dashboard Cite

Background-Inflammation is important to vascular repair following injury, modulating neointimal proliferation and remodeling. Previously, we have shown that a low-intensity inflammatory response aggravates neointimal formation following balloon and stent injury. The present study examined whether modulation of the extent and timing of nonspecific inflammation mediates the local vascular response in an additive unidirectional or rather a bidirectional fashion.Methods and results-Rabbits subjected to denudation and balloon injury of the iliac artery were treated with low(1 µg/kg) or high (100µg/kg) doses of bacterial endotoxin (LPS) immediately after injury, or with early high-dose LPS administered 3 days prior to injury (preconditioning). Neointimal formation at 28 days was significantly increased in the low-dose group (0.537 ± 0.059mm 2 ) as compared with controls (0.3 ± 0.03mm 2 ). High-dose LPS did not significantly affect neointimal formation while early high dose significantly reduced neointima (0.296 ± 0.033 and 0.194 ± 0.025mm 2 , respectively, n = 12-14/group). Arterial wall and systemically circulating interleukin-1β levels, and monocyte CD14 activation correlated with neointimal formation. Vascular remodeling was accelerated in animals treated with low-or high-dose LPS while not affected in the preconditioned group. Remodeling index inversely correlated with arterial matrix metalloproteinase-2 levels 6 days after injury.Conclusions-The extent and timing of nonspecific inflammation that is concurrent with vascular injury can determine different and opposite vascular repair patterns.

show abstract

“…5,6 Moreover, IL-1ra-deficient mice are more prone to neointima development after endothelial injury and more prone to atherogenesis. 7,8 Administration of IL-1 to porcine coronary arteries leads to neointimal formation, whereas balloon angioplasty results in increased levels of IL-1␤ at the injured segment of the porcine coronary artery but not at uninvolved sites.…”

Section: Cardiac-related Effects Of Il-1 and Il-1ramentioning

confidence: 99%

Inflammation and Cardiovascular Disease

Fearon

2008

Circulation

140

View full text Add to dashboard Cite

Interleukin-1β and Signaling of Interleukin-1 in Vascular Wall and Circulating Cells Modulates the Extent of Neointima Formation in Mice

Cited by 109 publications

References 36 publications

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

Inflammation and Cardiovascular Disease

Contact Info

Product

Resources

About