title: Circulating angiogenic cell dysfunction in patients with hereditary hemorrhagic telangiectasia.
abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder. Circulating angiogenic cells (CACs) play an important role in vascular repair and regeneration. This study was designed to examine the function of CACs derived from patients with HHT. Peripheral blood mononuclear cells (PBMNCs) isolated from patients with HHT and age- and gender-matched healthy volunteers were assessed for expression of CD34, CD133 and VEGF receptor 2 by flow cytometry. PBMNCs were cultured to procure early outgrowth CACs. Development of endothelial cell (EC) phenotype in CACs was analyzed by fluorescence microscopy. CAC apoptosis was assayed with Annexin V staining, and CAC migration assessed by a modified Boyden chamber assay. mRNA expression of endoglin (ENG), activin receptor-like kinase-1 (ACVLR1 or ALK1) and endothelial nitric oxide synthase (eNOS) in CACs was measured by real time RT-PCR. The percentage of CD34+ cells in PBMNCs from HHT patients was significantly higher than in PBMNCs of healthy controls. CACs derived from patients with HHT not only showed a significant reduction in EC-selective surface markers following 7-day culture, but also a significant increase in the rate of basal apoptosis and blunted migration in response to vascular endothelial growth factor and stromal cell-derived factor-1. CACs from HHT patients expressed significantly lower levels of ENG, ALK1 and eNOS mRNAs. In conclusion, CACs from patients with HHT exhibited various functional impairments, suggesting a reduced regenerative capacity of CACs to repair the vascular lesions seen in HHT patients.
authors.affiliation: Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada ; St. George's Hospital Trust, South Thames Foundation School, London, United Kingdom.
authors.forename: Liana
authors.initials: L
authors.lastname: Zucco
authors.affiliation: Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Qiuwang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuliszewski
authors.affiliation: Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kandic
authors.affiliation: Division of Respirology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Faughnan
authors.affiliation: Ottawa Health Research Institute, Ottawa, Ontario, Canada.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kutryk
mesh_terms: D000071916:AC133 Antigen; D030301:Activin Receptors, Type II; D000328:Adult; D017304:Annexin A5; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001808:Blood Vessels / Q000473:pathology* / Q000502:physiology; D000071063:Endoglin; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D052250:Nitric Oxide Synthase Type III; D010455:Peptides / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D000071916:AC133 Antigen; D017304:Annexin A5; D015703:Antigens, CD; D018952:Antigens, CD34; C064206:ENG protein, human; D000071063:Endoglin; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011956:Receptors, Cell Surface; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II