Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension.
Vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH) involves hyperproliferative and apoptosis-resistant pulmonary artery endothelial cells. In this study, we evaluated the relative contribution of bone marrow-derived proangiogenic precursors and tissue-resident endothelial progenitors to vascular remodeling in IPAH. Levels of circulating CD34+ CD133+ bone marrow-derived proangiogenic precursors were higher in peripheral blood from IPAH patients than in healthy controls and correlated with pulmonary artery pressure, whereas levels of resident endothelial progenitors in IPAH pulmonary arteries were comparable to those of healthy controls. Colony-forming units of endothelial-like cells (CFU-ECs) derived from CD34+ CD133+ bone marrow precursors of IPAH patients secreted high levels of matrix metalloproteinase-2, had greater affinity for angiogenic tubes, and spontaneously formed disorganized cell clusters that increased in size in the presence of transforming growth factor-beta or bone morphogenetic protein-2. Subcutaneous injection of NOD SCID mice with IPAH CFU-ECs within Matrigel plugs, but not with control CFU-ECs, produced cell clusters in the Matrigel and proliferative lesions in surrounding murine tissues. Thus, mobilization of high levels of proliferative bone marrow-derived proangiogenic precursors is a characteristic of IPAH and may participate in the pulmonary vascular remodeling process.
Asosingh
Kewal
K
Cleveland Clinic, Department of Pathobiology, NC22, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Aldred
Micheala A
MA
Vasanji
Amit
A
Drazba
Judith
J
Sharp
Jacqueline
J
Farver
Carol
C
Comhair
Suzy A A
SA
Xu
Weiling
W
Licina
Lauren
L
Huang
Lan
L
Anand-Apte
Bela
B
Yoder
Mervin C
MC
Tuder
Rubin M
RM
Erzurum
Serpil C
SC
D000071916:AC133 Antigen; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D016212:Transforming Growth Factor beta