Vascular Endothelial Cell Function Is Impaired in Neurofibromatosis 1 Patients

Jacquelyn K. Beals, PhD

November 02, 2009

November 2, 2009 (Honolulu, Hawaii) — A study has shown that human neurofibromatosis 1 (NF1) patients have an unusually large population of circulating proinflammatory cells, compared with controls. Previous research in genetically engineered mice has found that proinflammatory monocytic cells derived from NF1 ± bone marrow contribute to vascular disease, but the current study is the first to report the increased presence of proinflammatory monocytes in humans with NF1.

"We didn't know about it until we did the study," said Kimberly Ann Jett, BA, PhD student from the Department of Medical Genetics, Child and Family Research Institute, University of British Columbia in Vancouver.

Ms. Jett presented the results of a clinical study of NF1 patients here at the American Society of Human Genetics 59th Annual Meeting. "All of our [NF1] patients had proinflammatory cells," she told Medscape Pathology and Lab Medicine.

NF1 is an autosomal dominant disease caused by mutations in a tumor-suppressor gene, NF1.

Symptoms include café-au-lait spots on the skin, freckles in skin areas not exposed to sun, and pigmented bumps on the iris. Neurofibromas are nearly always benign and develop along nerves anywhere in the body. Optic pathway gliomas occur in about 30% of people with NF1. Other NF1-related symptoms include skeletal abnormalities and learning disabilities.

NF1 vascular disease is often asymptomatic and might first be identified in a life-threatening or fatal event. It has been attributed to haploinsufficiency of neurofibromin (a protein coded for by the NF1 gene) in endothelial cells, vascular smooth muscle, and inflammatory cells derived from the bone marrow. NF1 vasculopathy involves hyperplasia of both smooth muscle and endothelial layers, narrowing the lumens of vessels. The respective roles of endothelial and muscle layers in human NF1 vasculopathy were not previously understood.

The current study consisted of 8 NF1 patients, 4 with a history of vascular disease and 4 without vasculopathy. Among vasculopathies represented in the 4 patients were aortic stenosis, stroke, and ischemic attacks. The investigators performed flow-mediated vasodilation (FMD) and glyceryl-trinitrate-mediated dilation (nitroglycerin-mediated dilation; NMD) to determine the mechanism underlying vascular dysfunction.

FMD evaluates vascular endothelial dysfunction by measuring the dilation of smooth muscle in response to endothelial signaling. The response to occlusion-induced hypoxia was also measured. FMD was reduced in all 8 NF1 patients tested, indicating impaired function of the endothelium.

NMD indicates vascular smooth muscle dilation that occurs independent of the endothelium. Investigators gave nitroglycerin sublingually and obtained normal dilation by vascular smooth muscle relaxation in all patients but 1, who also had atherosclerotic disease. Overall, the tests demonstrated that NF1 vascular dysfunction is due to vascular endothelial rather than smooth muscle dysfunction.

The study also assessed patients for proinflammatory cells associated with vascular disease. Peripheral monocytic cells were sorted by polychromatic flow cytometry to identify CD16++ and CD14+ proinflammatory monocytes. A notable increase in CD16++ CD14+ proinflammatory monocytes was found in the peripheral blood of all 8 NF1 patients, but not in the control subjects.

"We didn't look at tumor load for these patients, so we don't know if [proinflammatory monocyte counts] increased based on tumor load," Ms. Jett told Medscape Pathology and Lab Medicine. Noting that their NF1 patients with vascular disease had slightly lower FMD than the patients without it, Ms. Jett acknowledged that "since we only had 8 patients, we don't know if it's significant. We'll need more patients to see if it's a general feature of people with NF1 or if it does relate to their disease and the extent of vascular disease they may have."

"With neurofibromatosis, the emphasis originally was on the tumors," said Frank J. Probst, MD, PhD, comoderator of the session, and assistant professor in the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston in Texas, talking with Medscape Pathology and Lab Medicine.

"Now that we've got a much better handle on the tumors and how to treat the tumors, I think that [Ms. Jett] is exploring another aspect of the disease that people haven't focused on quite as much. . . . It's a different perspective on a disease than a lot of people have," said Dr. Probst. "She's exploring something that people haven't really pursued as much in the past."

Dr. Jett has disclosed no relevant financial relationships. Dr. Probst reports receiving research or other grants, scholarships, or fellowships from the Burroughs Wellcome Fund.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 203. Presented October 23, 2009.

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